Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH:5]([CH2:9][CH3:10])[C:6]([OH:8])=[O:7].[Si:15]([O:22][C@H:23]1[CH2:32][C@H:31](O)[C@H:30]2[C:25]([CH:26]=[CH:27][C@H:28]([CH3:51])[C@@H:29]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[CH2:37]2)=[CH:24]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>>[Si:15]([O:22][C@H:23]1[CH2:32][C@H:31]([O:7][C:6](=[O:8])[CH:5]([O:4][C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=2[F:1])[CH2:9][CH3:10])[C@H:30]2[C:25]([CH:26]=[CH:27][C@H:28]([CH3:51])[C@@H:29]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:45])[CH3:46])[CH2:37]2)=[CH:24]1)([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16]
Reactant: CCC(Oc1ccccc1F)C(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: CCC(Oc1ccccc1F)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 98 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 0.72 g of (2RS)-2-(2-fluorophenoxy)butyric acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.30 g of the title compound as a colorless foam.
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[CH3:8][C:9]1[S:13][C:12]2[CH:14]=[C:15]3[C:20](=[C:21]([C:22]4[CH:27]=CC(O)=[CH:24][CH:23]=4)[C:11]=2[C:10]=1[CH3:29])[CH:19]=[CH:18][CH:17]=[CH:16]3.Cl>N1C=CC=CC=1>[CH3:8][C:9]1[S:13][C:12]2[CH:14]=[C:15]3[C:20](=[C:21]([C:22]4[CH:27]=[CH:6][C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:24][CH:23]=4)[C:11]=2[C:10]=1[CH3:29])[CH:19]=[CH:18][CH:17]=[CH:16]3
Reactant: Cc1sc2cc3ccccc3c(-c3ccc(O)cc3)c2c1C
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(-c2c3ccccc3cc3sc(C)c(C)c23)cc1
Yield: 87.4 %

Procedure:
Acetic anhydride (0.68 mL, 7.20 mmol) was added to a 0° C., stirred solution of 4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol (2.0 g, 6.57 mmol) in pyridine (8.6 mL). After 17 h the reaction mixture was added to 5% aqueous HCl and the resulting solid was filtered and washed with 5% aqueous HCl, water and triturated with pet. ether. It was then dried in vacuo to provide the title compound as a white solid (1.99 g, 88%): mp: 147-150° C.; NMR (DMSO-d6); δ 8.49 (s, 1H), 7.94 (d, J=8 Hz, 1H), 7.46 (ddd, J=8, 6, 2, 1H), 7.38 (ddd, J=8, 1, 1 Hz, 1H), 7.39-7.34 (m, 2H), 7.28 (d, J=8 Hz, 2H), 6.90 (d, J=9 Hz, 2H), 2.40 (d, J=1 Hz, 3H), 2.34 (s, 3H), 1.57 (d, J=1 Hz, 3H); MS (EI): 346 (90%, MI), 304 (100%); Anal. Calc. for C22H18O2S: C, 76.27, H, 5.34, N. 0.00. Found: C, 75.88, H. 5.04, N, 0.28.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[O:4]1.[Cl-].[Al+3].[Cl-].[Cl-].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>ClCCCl>[C:24]([C:15]1[CH:16]=[CH:17][C:5]2[O:4][CH:3]([C:2]([F:1])([F:18])[F:19])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]=2[CH:14]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)C1=Cc2ccccc2OC1C(F)(F)F
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)C1=Cc2cc(C(=O)c3ccccc3)ccc2OC1C(F)(F)F
Temperature: 80 °C
Reaction time: 4 h
Yield: 11.9 %

Procedure:
Ethyl 2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 10, Step 1) (1.59 g, 5.8 mmol) was dissolved in; 1,2-dichloroethane (3 mL) and added to a 0° C. suspension of aluminum chloride (2.59 g, 19.4 mmol) in 1,2-dichloroethane (3 mL). A solution of benzoyl chloride (1.01 g, 7.2 mmol) in 1,2-dichloroethane (3 mL) was added and the reaction was heated to 80° C. and stirred for 4 hours. The solution was poured onto 3 N HCl and ice and extracted with ethyl acetate. The ethyl acetate layers were combined, washed with 3N HCl saturated sodium bicarbonate, brine, dried over MgSO4 and concentrated in vacuo. The crude ester was purified by flash chromatography over silica gel (with 1:9 ethyl acetate/hexane as eluant) to afford the ester as a white crystalline solid (0.26 g, 12%): mp 114.7–116.1° C. 1H NMR (CDCl3/300 MHz) 7.82 (dd, 1H, J=8.5 Hz 2.0 Hz), 7.76 (m, 4H), 7.61 (m, 1H), 7.50 (m, 2H), 7.09 (d, 1H, J=8.7 Hz), 5.79 (q, 1H, J=6.8 Hz), 4.34 (m, 2H), 1.36 (t, 3H, J=7.2 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[CH3:10].[C:11](OCC)(=[O:13])[CH3:12].C(N)(=O)C>CCCCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:11](=[O:13])[CH3:12])=[CH:5][C:4]=1[CH3:10]
Reactant: CCOC(C)=O
Reactant: COc1ccc(N)cc1C
Agent: CC(N)=O
Solvent: CCCCC
Product: COc1ccc(NC(C)=O)cc1C

Procedure:
By proceeding in a manner similar to Reference Example 33(a) above but using 4-methoxy-3-methyl-phenylamine (2.07 g, Reference Example 30(u)) and subjecting the reaction product to flash chromatography on silica eluting with a mixture of ethyl acetate and n-pentane (1:1, v/v) there was prepared N-4-methoxy-3-methyl-phenyl)-acetamide (2.65 g) as a pale pink crystalline solid. LC-MS (Method J): RT=2.94 minutes, 180.30 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH:10]=[C:11]([C:13]([N:15]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)=[O:14])[N:12]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([Mg]Br)=[CH:32][CH:31]=1.[NH4+].[Cl-].O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[CH:10]=[C:11]([C:13]([N:15]2[CH2:16][CH2:17][C:18]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)([OH:21])[CH2:19][CH2:20]2)=[O:14])[N:12]=1
Reactant: O=C1CCN(C(=O)c2cn(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)n2)CC1
Reactant: Fc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1)N1CCC(O)(c2ccc(F)cc2)CC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
A solution of 1-{[2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazol-4-yl]carbonyl}-4-piperidinone (0.1 g, 0.24 mmol, prepared as described in Example 13) in THF (4 mL) was added dropwise to a solution of 4-fluorophenylmagnesium bromide (0.6 mL, 0.60 mL) at −78° C. The mixture was stirred at −78° C. for 2 h then allowed to warm up to 30° C. Saturated NH4Cl (3 mL) was added slowly followed by water (3 mL). The mixture was extracted with ethyl acetate (3×20 mL) and dried over MgSO4. The product (0.056 g, 46%) was isolated by column (50% ethyl acetate in hexane). MS (Electrospray) 510.1 (M)+; 1H NMR (300 MHz, CD2Cl2) δ 7.81 (s, 1H), 7.50-7.24 (m, 8H), 7.10-6.98 (m, 4H), 5.33-5.17 (m, 1H), 4.74-4.57 (m, 1H), 3.68 (t, 1H), 3.31 (t, 1H), 2.15 (br, 2H), 1.83 (d, 2H).
Reaction SMILES: C1CCCCCCC1.[CH2:9]1[CH:18]2[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12][CH2:11][CH2:10]1>>[CH:17]1[C:18]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: C1CCC2CCCCC2C1
Solvent: C1CCCCCCC1
Product: c1ccc2ccccc2c1

Procedure:
Similarly, when Example 2(a) is repeated except that cyclooctane is replaced by a stoichiometrically equivalent amount of decalin, a corresponding yield of naphthalene is obtained.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:31])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]#[N:30])[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:11]1[C:12]([N:14]([CH3:16])[CH3:15])=[CH:13][C:8]2[N:7]=[C:21]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([C:29]#[N:30])[CH:24]=3)[CH2:20][C:19](=[O:31])[NH:18][C:9]=2[CH:10]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(C#N)c2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1ccnc(C#N)c1)=N2

Procedure:
The title compound was prepared from {4-chloro-2-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-5-dimethylamino-phenyl}-carbamic acid tert.-butyl ester (Example M15) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (50 mg).
Reaction SMILES: Cl.Cl.[CH2:3]([NH:10][NH2:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])(=O)C.[Na+].O.[N:18]1[C:26]2[CH:25]=[CH:24][N:23]=[CH:22][C:21]=2[NH:20][C:19]=1[C:27]1[C:39]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32](=O)[C:31]=2[CH:30]=[CH:29][CH:28]=1>CO>[CH2:3]([NH:10][N:11]=[C:32]1[C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([C:19]3[NH:18][C:26]4[CH:25]=[CH:24][N:23]=[CH:22][C:21]=4[N:20]=3)[C:39]=2[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NNCc1ccccc1
Reactant: O=C1c2ccccc2-c2c1cccc2-c1nc2ccncc2[nH]1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: c1ccc(CNN=C2c3ccccc3-c3c2cccc3-c2nc3cnccc3[nH]2)cc1
Temperature: 52.5 °C
Yield: 27.4 %

Procedure:
In a 10-ml round-bottomed flask, dissolve 100 mg of 4-(3H-imidazo[4,5-c]pyridin-2-yl)-fluoren-9-one, obtained in Example 1, in 3 ml of methanol, then add successively 197 mg of benzylhydrazine dihydrochloride and 138 mg of dry sodium acetate and heat at 50-55° C. for 5 hours. Pour the cooled reaction mixture into 10 ml of water, extract with ethyl acetate then twice with dichloromethane. Combine the organic phases, wash with a saturated aqueous solution of sodium chloride, dry over sodium sulphate then concentrate under reduced pressure. After purification by chromatography on silica gel (40-63 μm), eluting with a mixture of dichloromethane and methanol (93-7 by volume), we obtain 37 mg of N-benzyl-N′-[4-(1H-imidazo[4,5-c]pyridin-2-yl)-fluoren-9-ylidene]-hydrazine, in the form of a yellow foam with the following characteristics:
Reaction SMILES: N(CCO)(CCO)CC[OH:4].OC[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[Na].[Br:24][C:25]1[C:26]([Br:38])=[C:27]([Br:37])[C:28]([Br:36])=[C:29]2[C:34](=[O:35])[O:33][C:31](=[O:32])[C:30]=12.[OH-].[K+:40]>O>[Br:24][C:25]1[C:26]([Br:38])=[C:27]([Br:37])[C:28]([Br:36])=[C:29]([C:34]([O-:33])=[O:35])[C:30]=1[C:31]([O-:4])=[O:32].[K+:40].[K+:40]
Reactant: O=C1OC(=O)c2c(Br)c(Br)c(Br)c(Br)c21
Reactant: OCCN(CCO)CCO
Agent: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: [K+]
Agent: [Na]
Solvent: O
Product: O=C([O-])c1c(Br)c(Br)c(Br)c(Br)c1C(=O)[O-]
Temperature: 75 °C

Procedure:
A stainless steel kettle equipped with good agitation, heating and cooling was charged with 100 lbs. of water, 20 lbs. of polyethylene glycol (M.W. 200), 21/2 lbs. of triethanolamine, 421/2 lbs. of a non-ionic emulsifying agent (alkoxylated aryl polymer) and 40 lbs. of sorbitol. After mixing wascomplete, 10 lbs. of an anionic dispersing agent (the sodium salt of a formaldehyde-naphthalane sulfonic acid condensate) was added and the mixture stirred until all these additions were dissolved. With continued stirring, 500 lbs. of tetrabromophthalic anhydride were then added and mixed until uniformily dispersed. 1211/2 lbs. of 45 percent KOH were then added. The reaction was exothermic. The mix was then heated to about 90°-95° C. and stirring continued at 90°-95° C. until a smooth soft uniform paste was formed. The mix was then cooled to 75° C. and 1631/2 lbs. of a 2.6 percent Xanthan gum solution wasadded, the mix stirred until uniform and water added as necessary to make 1000 lbs. of paste. The resultant product was a smooth soft uniform paste of 65-66 percent solids, pH 2-3. A 5 percent aqueous dispersion of this product also had a pH of 2-3. One percent of the paste added to boiling water gave an almost clear solution with a pH of 2-3.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]([OH:13])=O)[C:6]=2[N:7]=1.[N:14]1[C:23]2[C:18](=[CH:19][C:20]([NH2:24])=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1.C(N(CC)C(C)C)(C)C.C1CN(C(ON2N=NC3C2=CC=CC=3)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl.O.CN(C)C=O>[N:14]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:11]([C:8]3[C:6]4[N:7]=[C:2]([Cl:1])[N:3]=[CH:4][C:5]=4[S:10][CH:9]=3)=[O:13])=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1csc2cnc(Cl)nc12
Reactant: Nc1ccc2ncccc2c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2OC(N1CCCC1)=[N+]1CCCC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc2ncccc2c1)c1csc2cnc(Cl)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 0.050 g (0.233 mmole) 2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid, 0.0672 g (0.466 mmole) of quinolin-6-amine, 0.122 mL (0.699 mmole) of N,N-diisopropylethylamine and 1.55 mL of dimethylformamide was added 0.111 g (0.256 mmole) of O-(benzotriazol-1-yl)-N,N,N′,N′-bis(tetramethylene)uronium hexafluorophosphate. The mixture was stirred at room temperature for 2 hours. Water and dichloromethane were added. The aqueous layer was washed three times with dichloromethane. The combined organic layer was washed with aqueous sodium carbonate, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dried in high vacuum to give 2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid quinolin-6-ylamide as a yellow-greenish solid
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([NH:11]C=O)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][P:20]([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])=[O:21].[NH3:28]>>[NH2:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][N:6]2[O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][P:20]([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])=[O:21])=[C:2]([NH2:28])[N:10]=1
Reactant: CCOP(=O)(COCCCOn1cnc2c(Cl)nc(NC=O)nc21)OCC
Reactant: N
Product: CCOP(=O)(COCCCOn1cnc2c(N)nc(N)nc21)OCC
Yield: 32 %

Procedure:
A solution of 6-chloro-9-[3-(diethoxyphosphorylmethoxy)propoxy]-2-formamidopurine (1.2 g, 2.85 mmol) in ethanolic ammonia (25 ml) was heated at 110° C. in an autoclave for 7.5 h then left to cool for 12 h. The reaction was then evaporated in vacuo and the residue chromatographed on silica eluting with chloroform/methanol (10:1) to give 2,6-diamino-9-[3-(diethoxyphosphorylmethoxy)propoxy]purine as a pale yellow solid (0.34 g, 32%); νmax (KBr) 3313, 3149, 1586, 1481, 1240, 1054 cm-1 ; δH [(CD3)2SO] 1.22(6H, t, J7 Hz,(CH3CH2O)2), 1.91(2H, m, CH2CH2CH2), 3.70(2H, t, J6 Hz, CH2OCH2P), 3.84(2H, d, J7.98 Hz,CH2P), 4.04(4H, m,(CH3CH2O)2), 4.31(2 H, t, J6.5 Hz, NOCH2), 5.93(2H, br.s, D2O exchangeable, NH2), 6.77(2H, br.s, D2O exchangeable, NH2), 7.94(1H, s, H-8); Found C, 41.25; H, 6.32; N, 22.65%; M+ 374.1477; C13H23N6O5P.0.2H2O requires: C, 41 31; H, 6.35; N, 22.24%; M+ 374.1468.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[S:15]([NH:18][C:19]1[CH:24]=[C:23]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:22]([CH3:42])=[CH:21][C:20]=1[OH:43])(=[O:17])=[O:16].[Cl-].[NH4+].O>[Fe].C(O)(C)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[S:15]([NH:18][C:19]1[CH:24]=[C:23]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:22]([CH3:42])=[CH:21][C:20]=1[OH:43])(=[O:16])=[O:17]
Reactant: CCCCCCCCCCCCCCCCOc1cc(NS(=O)(=O)c2cc([N+](=O)[O-])ccc2OCCOC)c(O)cc1C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCCCOc1cc(NS(=O)(=O)c2cc(N)ccc2OCCOC)c(O)cc1C
Reaction time: 1 h

Procedure:
32 g of 2-[2'-(2-methoxyethoxy)-5'-nitrobenzenesulfonamido]-4-hexadecyloxy-5-methylphenol prepared as described in Step (b) above, 24 g of iron powder, 12 g of Fe3O4, 0.6 g of ammonium chloride and 25 ml of water were added to 300 ml of isopropyl alcohol and the mixture was refluxed on a steam bath with stirring for 1 hour. After completion of the reaction, the mixture was filtered while hot and the filtrate was cooled with ice. The crystals thus precipitated were recovered by filtration, washed with 50 ml of isopropyl alcohol and air-dried. Yield: 23 g. Melting Point: 142° to 144° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:19])([F:18])[C:9]([F:17])([F:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[N:20]1C2C(=CC=CC=2)C=C[CH:21]=1>CN(C)C=O>[F:18][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:21]#[N:20])([F:19])[C:9]([F:17])([F:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: FC(F)(c1ccccc1)C(F)(F)c1ccccc1Br
Reactant: c1ccc2ncccc2c1
Solvent: CN(C)C=O
Product: N#Cc1ccccc1C(F)(F)C(F)(F)c1ccccc1

Procedure:
A mixture of 3.33 g. (0.01 mole) of 2-bromo-α,α,α',α'-tetrafluorobibenzyl, 2.70 g. of cuprous cyanide, 30 ml. of dry quinoline, and 3 ml. of dry dimethylformamide are stirred and heated to refluxing for about 30 hours. After cooling and dilution with ether, the precipitate is removed by filtration and washed with ether. Solvents are evaporated from the filtrate under reduced pressure leaving the product as an oily brown solid. Purification is effected by column chromatography on 150 g. of silica, the product being eluted with benzene-hexane (3:1). The fractions which show one spot of rf 0.7 on a silica thin layer plate developed with benzene are combined. Evaporation of the solvents under reduced pressure leaves white crystals, m.p. 84°-86°C. A sample for analysis is sublimed at 55°C. and 0.05 mm; m.p. 85°-86°C.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:22](=[O:23])[N:6]2[C:7]([C:19]([OH:21])=[O:20])=[C:8]([C:11]3[S:15][C:14]4=[CH:16][N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].C(=O)([O-])O.[Na+].[C:29]([O:35][CH2:36]I)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]>O.CN(C=O)C.C(OCC)(=O)C>[OH:1][C@@H:2]([C@H:4]1[C:22](=[O:23])[N:6]2[C:7]([C:19]([O:21][CH2:36][O:35][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[O:20])=[C:8]([C:11]3[S:15][C:14]4=[CH:16][N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(c3cn4cncc4s3)[C@H](C)[C@H]12
Reactant: CC(C)(C)C(=O)OCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(c3cn4cncc4s3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 947 mg of (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylic acid in 180 ml of water was added 7.8 ml of 0.1 N aqueous sodium hydrogen carbonate, and the mixture was stirred at room temperature for 2 hours to form a solution, which was then frozen. The frozen solution was dissolved in 12 ml of dry DMF, mixed with 0.36 ml of iodomethyl pivalate under the atmosphere of argon at −30° C., and stirred for 1.5 hours during which the temperature was raised up to −10° C. The reaction mixture was diluted with 100 ml of ethyl acetate, and washed with 100 ml of semi-saturated aqueous saline. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to a total volume of 5 ml. The residue thus obtained was purified by column chromatography on silica gel (chloroform:methanol 10:1) and on Sephadex LH-20 (chloroform:methanol=1:1) in this sequence to give 576 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[N:12]1[C:20]2[C:15](=[C:16]([CH3:22])[CH:17]=[C:18]([CH3:21])[N:19]=2)[C:14](C#N)=[CH:13]1>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[N:12]1[C:20]2[C:15](=[C:16]([CH3:22])[CH:17]=[C:18]([CH3:21])[N:19]=2)[CH:14]=[CH:13]1
Reactant: COc1cc(Br)c(-n2cc(C#N)c3c(C)cc(C)nc32)c(OC)c1
Agent: O=S(=O)(O)O
Product: COc1cc(Br)c(-n2ccc3c(C)cc(C)nc32)c(OC)c1
Yield: 5.9 %

Procedure:
A mixture of 200 mg of 1-(2-bromo-4,6-dimethoxyphenyl)-3-cyano-4,6-dimethyl-7-azaindole and 10 ml of 65% sulfuric acid was refluxed for one hour. The mixture was worked up as described in Example 65 to give 185 mg of crude product. A 40 mg portion was purified by preparative liquid chromatography on a nitrile column using 95:5 1-chlorobutane-acetonitrile to give 11 mg of 1-(2-bromo-4,6-dimethoxyphenyl)-4,6-dimethyl-7-azaindole. Mass spec: (M+H)+ =360.9; calculated, 361.1.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[P:6](Cl)([Cl:9])([Cl:8])=[S:7]>CCOCC>[Cl:8][P:6]([Cl:9])([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[S:7]
Reactant: S=P(Cl)(Cl)Cl
Reactant: C1CCNC1
Solvent: CCOCC
Product: S=P(Cl)(Cl)N1CCCC1
Temperature: 25 °C
Yield: 79.6 %

Procedure:
A solution of 43.4 mL (0.52 mol) of pyrrolidine in 50 mL of ether was added dropwise to a stirred solution of 116 mL (1.04 mol) of thiophosphoryl chloride in 200 mL of ether at 0° C. (ice bath) under an argon atmosphere. After the addition was completed, the resultant slurry was slowly warmed to room temperature overnight. A trace of pyrrolidinium hydrochloride was removed by filtration and the filtrate was concentrated under vacuum to provide 84.5 g of a clear oil. A portion of this oil (40 g) was distilled at 80° C. (0.25 mm) to provide 18.1 g of the desired dichloride as a clear oil.
Reaction SMILES: [OH:1][C:2]1[CH:21]=[C:20]([O:22][CH2:23][CH2:24][OH:25])[CH:19]=[CH:18][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[S:5].[C:26]([C:34]1[CH:44]=[CH:43][C:37]([O:38][CH2:39][C:40](O)=[O:41])=[CH:36][C:35]=1[OH:45])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:26]([C:34]1[CH:44]=[CH:43][C:37]([O:38][CH2:39][C:40]([O:25][CH2:24][CH2:23][O:22][C:20]2[CH:19]=[CH:18][C:3]([C:4](=[S:5])[C:6]3[CH:11]=[CH:10][C:9]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:8][CH:7]=3)=[C:2]([OH:1])[CH:21]=2)=[O:41])=[CH:36][C:35]=1[OH:45])(=[O:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(O)COc1ccc(C(=O)c2ccccc2)c(O)c1
Reactant: OCCOc1ccc(C(=S)c2ccc(-c3ccccc3)cc2)c(O)c1
Product: O=C(COc1ccc(C(=O)c2ccccc2)c(O)c1)OCCOc1ccc(C(=S)c2ccc(-c3ccccc3)cc2)c(O)c1

Procedure:
Following the general procedure of Example 17, the title compound is prepared by reacting equimolar amounts of the alcohol compound of Example 7 and 4-benzoyl-3-hydroxyphenoxyacetic acid.
Reaction SMILES: [O:1]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.I[CH:17]([CH3:19])[CH3:18].[OH-].[K+]>C(O)C.O>[CH:17]([O:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:3][CH:4]=1)([CH3:19])[CH3:18]
Reactant: Oc1ccc(Oc2ccc(O)cc2)cc1
Reactant: CC(C)I
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)Oc1ccc(Oc2ccc(O)cc2)cc1
Yield: 443.1 %

Procedure:
To a mixture of 4,4′-oxydiphenol (3.680 g, 1.82 mmol) and 2-iodopropane (1.82 mL, 1.82 mmol) in ethanol (8.0 mL) at refluxing was added KOH (88%, 1.22 g, 1.91 mmol, 1.05 equivalents) in water (4.0 mL) over a period of 10 min. The resulting mixture was refluxed for 1 hour. Ethanol was removed. The residue was dissolved in ether, which was washed with brine (1×), dried over MgSO4 and concentrated. The residue was purified on a silica gel column eluting with ethyl acetate and hexane gradient to give the title product as a white solid (1.970 g, 44%)
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[I:12]Cl.O>CC(O)=O>[I:12][C:9]1[CH:10]=[C:4]([O:3][CH:2]([F:11])[F:1])[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: Nc1ccc(OC(F)F)cc1
Reactant: ClI
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(OC(F)F)cc1I
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 22.3 %

Procedure:
A solution of 4-(difluoromethoxy)aniline (1.0 g, 6.30 mmol) in AcOH (6 mL) was heated to 60° C. and iodine monochloride (1.07 g, 6.6 mmol) in AcOH (15 mL) was added dropwise. The reaction mixture was then heated to 85° C. and stirred for 1.5 h. The reaction mixture was cooled to r.t. and poured into cold water and the resulting suspension filtered. The filtrate was concentrated in vacuo to give a dark brown oil. Purification by column chromatography (SiO2, 10-20% EtOAc/hexanes) gave the title compound (0.40 g, 22%) as a dark brown oil. δH (DMSO-d6) 7.38 (1H, d, J 2.7 Hz), 6.98-6.94 (1H, m), 6.97 (1H, t, J 74.8 Hz), 6.75 (1H, d, J 8.8 Hz), 5.20 (2H, br. s). LCMS (ES+) 286.0 (M+H)+, RT 3.28 minutes (Method 5).