Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][C:16]([OH:18])=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CN(C)CCCN=C=NCC.[CH3:31][Si:32]([CH3:37])([CH3:36])[CH2:33][CH2:34]O>C(Cl)Cl>[CH3:31][Si:32]([CH3:37])([CH3:36])[CH2:33][CH2:34][O:17][C:16](=[O:18])[CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)CCO
Reactant: O=C(O)COCCOCCOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: C[Si](C)(C)CCOC(=O)COCCOCCOCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 97.5 %

Procedure:
10-Phenyl-3,6,9-trioxadecanoic acid (1.71 g, 6.71 mmol) was dissolved in CH2Cl2 (13.4 mL) and the solution was cooled to 0° C. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (1.41 g, 7.38 mmol) and N,N-dimethylaminopyridine (DMAP) (41.0 mg, 0.34 mmol) were added, and the suspension was stirred for 10 minutes at 0° C. 2-(Trimethylsilyl)ethanol (872.4 mg, 7.38 mmol) was added dropwise via syringe, and the solution was stirred for 20 minutes while warming to room temperature. The reaction was quenched with H2O and extracted with Et2O (3×50 mL). The combined Et2O extracts were washed sequentially with 10% HCl (1×50 mL), 5% NaHCO3 (1×50 mL), and saturated NaCl (1×50 mnL), and dried over Na2SO4. Concentration followed by flash chromatography (silica, 4:1 hexanes/EtOAc) afforded 10-phenyl-3,6,9-trioxadecanoic acid 2-(trimethylsilyl)ethyl ester (2.32 g, 97% yield). Rf=0.26 (4:1 hexanes/EtOAc); IR (neat): 3500-3400, 3000-2700, 1751, 1733, 1615, 1455, 1250, 1148, 1124 cm−1; 1H NMR (300 MHz, CDCl3): δ 7.32-7.23 (m, 5H), 4.54 (s, 2H), 4.24-4.18 (m, 2H), 4.10 (s, 2H), 3.72-3.59 (m, 8H), 1.01-0.95 (m, 2H), 0.01 (s, 9H); 13C NMR (75 MHz, CDCl3): δ 170.5, 138.2, 128.3, 127.6, 127.5, 73.2, 70.8, 70.6, 69.4, 68.8, 63.0, 17.3, −1.6; LRMS (LSIMS, 3-NBA): m/z 377.2 [M+Na+, calc'd for C18H30O5NaSi 377.5].
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.CN(C)[CH:18]=[O:19].[Cl-].[NH4+]>C1COCC1>[Br:9][C:10]1[C:15]([CH:18]=[O:19])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: Brc1ccccn1
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1cccnc1Br
Reaction time: 2 h

Procedure:
Lithium diisopropylamide (1.0M in THF, 12.6 mmol) is added to a stirring solution of 2-bromopyridine (2.0 g, 12.6 mmol) in THF (10 ml) at -78° under nitrogen. The resulting mixture is stirred at -78° for two hours followed by addition of dimethylformamide (12.6 mmol) in THF (5 ml) at -78°. The mixture is allowed to warm to 20°-25°, poured into a saturated aqueous solution of ammonium chloride (100 ml), and extracted with ethyl acetate (3×50 ml). The organic phases are combined, dried over sodium sulfate and solvent removed under reduced pressure. The resulting residue is purified via flash chromatography (silica gel; hexane/ethyl acetate (4/1)) to give the title compound, mp 74°-76°; NMR (CDCl3) 7.45, 8.19, 8.59, 10.35δ; MS (EI, m/e) 185 (M+).
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:18])[O:9][C:10]3[C:15]([C:16]=2[OH:17])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26]Cl)[CH2:21][CH2:20]1>C(O)(C)C>[O:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][O:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[O:9][C:8](=[O:18])[C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:21][CH2:20]1
Reactant: ClCCN1CCOCC1
Reactant: O=c1oc2ccccc2c(O)c1-c1ccccc1
Solvent: CC(C)O
Product: O=c1oc2ccccc2c(OCCN2CCOCC2)c1-c1ccccc1
Yield: 80 %

Procedure:
By causing 100 g. (0.42 mol) of 3-phenyl-4-hydroxy-coumarin and 86.8 g. (0.55 mol) of 2-morpholino-1-chlorethane to react in the manner described in Example 1, 119 g. of a white solid are obtained. M.P. 97° C. (isopropanol), yield 80% (theoretical yield 147 g.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)C=O.[H-].[Na+].Cl.Cl[CH2:33][C:34]1[N:35]=[C:36]([CH3:39])[S:37][CH:38]=1>O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:33][C:34]3[N:35]=[C:36]([CH3:39])[S:37][CH:38]=3)[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Reactant: Cc1nc(CCl)cs1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(Cn2c(N3CCCN(C(=O)OC(C)(C)C)CC3)nc3ccccc32)cs1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.1 %

Procedure:
Treat a solution of 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepan (0.89 g, 2.77 mmol, Preparation 9) and dimethylformamide (10 mL) with sodium hydride (0.15 g, 3.05 mmol, 49% dispersion in oil ) at room temperature. After 15 minutes, add slowly a solution of 4-chloromethyl-2-methylthiazole hydrochloride (0.56 g, 3.05 mmol, Lancaster Synthesis) and dimethylformamide (10 mL). After stirring 12 hours at room temperature, add water (10 mL) slowly and extract with dichloromethane.(150 mL). Wash the organic phase with water (3×10 mL), dry (Na2SO4) the organic layer, filter, concentrate the filtrate to remove the solvent and purify the residue by chromatography on silica gel eluting with 5% methanol in dichloromethane. Concentrate the desired fractions to afford 1.02 g of 4-[1-(2-methyl-thiazol-4-ylmethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:28])[C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1.[CH2:37]([N:44]=[C:45]=[O:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:1]([O:8][C:9](=[O:29])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:28])[C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:45]([NH:44][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:46])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: O=C=NCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)NCc1ccccc1

Procedure:
N-(t-Butoxycarbonyl)-L-prolyl-L-proline benzyl ester (3.60 g) was treated with 4N hydrochloric acid/1,4-dioxane and then reacted with benzylisocyanate (1.2 ml) as in Example 21-B) to give 2.98 g of the title compound as crystals.
Reaction SMILES: [CH:1]12[CH:9]([C:10]3[CH:23]=[CH:22][C:13]([O:14][CH2:15][C@H:16]4[O:20][C:19]([NH2:21])=[N:18][CH2:17]4)=[CH:12][CH:11]=3)[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2.C([O:26][C:27](=O)[C:28]#[C:29][CH3:30])C>C(Cl)(Cl)Cl>[CH:1]12[CH:9]([C:10]3[CH:23]=[CH:22][C:13]([O:14][CH2:15][C@H:16]4[O:20][C:19]5=[N:21][C:27](=[O:26])[CH:28]=[C:29]([CH3:30])[N:18]5[CH2:17]4)=[CH:12][CH:11]=3)[CH:5]([CH2:4][CH2:3][CH2:2]1)[CH2:6][CH2:7][CH2:8]2
Reactant: CC#CC(=O)OCC
Reactant: NC1=NC[C@@H](COc2ccc(C3C4CCCC3CCC4)cc2)O1
Solvent: ClC(Cl)Cl
Product: Cc1cc(=O)nc2n1C[C@@H](COc1ccc(C3C4CCCC3CCC4)cc1)O2

Procedure:
The title compound was prepared from (S)-5-(4-bicyclo[3.3.1]non-9-yl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (see Example 20) and but-2-ynoic acid ethyl ester employing the procedure described in Example 95. [α]D25 −33.80 (c 0.5, CHCl3).
Reaction SMILES: Cl.[CH2:2]([NH:18][C:19]1[CH:29]=[CH:28][C:22]([CH2:23][CH2:24][C:25](Cl)=[O:26])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[NH3:30]>>[CH2:2]([NH:18][C:19]1[CH:29]=[CH:28][C:22]([CH2:23][CH2:24][C:25]([NH2:30])=[O:26])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)Cl)cc1
Reactant: N
Agent: Cl
Product: CCCCCCCCCCCCCCCCNc1ccc(CCC(N)=O)cc1

Procedure:
As in the method described in Example 31, 4-(hexadecylamino)hydrocinnamic acid chloride hydrochloride is treated with anhydrous ammonia to yield 4-(hexadecylamino)hydrocinnamamide.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:12][NH2:13].[CH3:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([CH:21]=[CH:22][C:23]2[C:31]3[C:26](=[CH:27][C:28]([NH:32][C:33]4[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=4[C:35](O)=[O:36])=[CH:29][CH:30]=3)[N:25]([CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)[N:24]=2)[CH:16]=1>>[CH3:2][N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:12][NH:13][C:35](=[O:36])[C:34]1[CH:38]=[CH:39][CH:40]=[CH:41][C:33]=1[NH:32][C:28]1[CH:27]=[C:26]2[C:31]([C:23]([CH:22]=[CH:21][C:17]3[CH:16]=[C:15]([CH3:14])[CH:20]=[CH:19][N:18]=3)=[N:24][N:25]2[CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)=[CH:30][CH:29]=1
Reactant: Cc1ccnc(C=Cc2nn(C3CCCCO3)c3cc(Nc4ccccc4C(=O)O)ccc23)c1
Reactant: Cn1c(CN)nc2ccccc21
Agent: Cl
Product: Cc1ccnc(C=Cc2nn(C3CCCCO3)c3cc(Nc4ccccc4C(=O)NCc4nc5ccccc5n4C)ccc23)c1

Procedure:
Prepared in a similar manner to that described for Example 6 above, except using C-(1-Methyl-1H-benzoimidazol-2-yl)-methylamine hydrochloride N and 2-[3-[2-(4-Methyl-pyridin-2-yl)-vinyl]-1-(tetrahydro-pyran-2-yl)-1H-indazol-6-ylamino]-benzoic acid. 1H NMR (DMSO-d6) δ 9.82 (1H, s), 9.20 (1H, t, J=5.3 Hz), 8.46 (1H, d, J=4.9 Hz), 8.07 (1H, d, J=8.9 Hz), 7.85 (1H, d, J=16.4 Hz), 7.74 (1H, d, J=7.3 Hz), 7.58 (1H, d, J=7.2 Hz), 7.50 (6H, m), 7.19 (4H, m), 6.92 (1H, t, J=8.1 Hz), 5.78 (1H, dd, J=2.5, 9.5 Hz), 4.79 (2H, d, J=5.5 Hz), 3.89 (1H,m), 3.83 (3H, s), 3.71 (1H, m), 2.41 (1H, m), 2.35 (3H, s), 2.00 (2H, m), 1.74 (1H, m), 1.57 (2H, m).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[C:6]([O:16][C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=[O:19])=[CH:5][CH:4]=1.Cl[CH2:24][C:25]1[CH:44]=[CH:43][C:28]([O:29][CH2:30][C:31]2[N:32]=[C:33]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[O:34][C:35]=2[CH3:36])=[C:27]([O:45][CH3:46])[CH:26]=1.Cl>O.CN(C)C=O>[CH3:46][O:45][C:27]1[CH:26]=[C:25]([CH:44]=[CH:43][C:28]=1[O:29][CH2:30][C:31]1[N:32]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:34][C:35]=1[CH3:36])[CH2:24][N:14]1[C:15]2[CH:3]=[CH:4][CH:5]=[C:6]([O:16][C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=[O:19])[C:7]=2[C:8]2[C:13]1=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: CC(C)(Oc1cccc2[nH]c3ccccc3c12)C(=O)O
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Cn2c3ccccc3c3c(OC(C)(C)C(=O)O)cccc32)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
302 mg of sodium hydride (60%) was added to N,N-dimethylformamide (30 mL) solution of 924 mg of 2-(9H-carbazole-4-yloxy)-2-methylpropionic acid, stirred at room temperature for 20 minutes. Thereafter, 1.31 g of 4-((4-(chloromethyl)-2-methoxyphenoxy)methyl)-5-methyl-2-phenyloxazole was added thereto, and stirred at room temperature for 1 hour. The reaction mixture was poured into water, adjusted to pH3 with 1 N hydrochloric acid, and extracted twice with ethyl acetate. The combined extract was washed with brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo, the residue was purified by silica gel chromatography (chloroform:methanol=50:1), and 1.88 g of the subject compound was prepared as pale yellow powder.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH:5]([O:33][CH2:34][CH3:35])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([CH3:31])([C:16]2[S:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[N:18][CH:17]=2)[CH3:15])=[CH:9][C:8]=1[CH3:32])C.[Li+].[OH-]>>[CH2:34]([O:33][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([CH3:31])([C:16]2[S:20][C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=3)=[N:18][CH:17]=2)[CH3:15])=[CH:9][C:8]=1[CH3:32])[C:4]([OH:36])=[O:3])[CH3:35]
Reactant: CCOC(=O)C(Cc1ccc(OC(C)(C)c2cnc(-c3ccc(C(F)(F)F)cc3)s2)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OC(C)(C)c2cnc(-c3ccc(C(F)(F)F)cc3)s2)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], [rac]-2-ethoxy-3-(2-methyl-4-{1-methyl-1-[2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenyl)-propionic acid ethyl ester was treated with LiOH to obtain [rac]-2-ethoxy-3-(2-methyl-4-{1-methyl-1-[2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenyl)-propionic acid as colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].[CH3:16][N:17]([CH3:21])[C:18](Cl)=[S:19]>>[CH3:16][N:17]([CH3:21])[C:18](=[S:19])[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:9])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CN(C)C(=S)Cl
Reactant: O=C(c1ccccc1)c1ccccc1O
Product: CN(C)C(=S)Oc1ccccc1C(=O)c1ccccc1
Yield: 81.8 %

Procedure:
Following the procedure described in Preparation Ia and starting from 9.5 g (0.048 mol) of 2-hydroxyphenyl phenyl methanone and 10.3 g (0.083 mol) of dimethylthiocarbamoyl chloride, 11.2 g of the expected product are obtained (yield: 82%).
Reaction SMILES: CO[N:3]=[C:4]1[C:12]2[C:7](=[CH:8][N:9]=[C:10]([Cl:13])[CH:11]=2)[O:6][CH2:5]1.B>C1COCC1>[Cl:13][C:10]1[CH:11]=[C:12]2[CH:4]([NH2:3])[CH2:5][O:6][C:7]2=[CH:8][N:9]=1
Reactant: CON=C1COc2cnc(Cl)cc21
Agent: B
Solvent: C1CCOC1
Product: NC1COc2cnc(Cl)cc21
Temperature: 40 °C

Procedure:
To a solution of 5-chlorofuro[2,3-c]pyridin-3(2H)-one O-methyl oxime (0.71 mmol) in 1 mL THF were added 2.2 mL of a borane solution (1M in THF). The mixture was heated to 40° C. for 1 h in a closed vessel. At RT, the reaction mixture was quenched with MeOH, the pH was adjusted to 9 with 1M NaOH solution and the mixture was extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the desired product as yellow oil;
Reaction SMILES: [S:1]1[C@@H:6]2[CH2:7][C:8](=[O:9])[N:5]2[CH2:4][CH:3]=[CH:2]1.S1[C@@H]2CC(=[O:18])N2C=CC1.ClC1C=CC=C(C(OO)=O)C=1>>[S:1]1(=[O:18])[C@@H:6]2[CH2:7][C:8](=[O:9])[N:5]2[CH:4]=[CH:3][CH2:2]1
Reactant: O=C1C[C@H]2SC=CCN12
Reactant: O=C1C[C@H]2SCC=CN12
Agent: O=C(OO)c1cccc(Cl)c1
Product: O=C1C[C@@H]2N1C=CCS2=O

Procedure:
The rearrangement of 2-cephem derivatives to the corresponding 3-cephem compounds is accomplished by an oxidation-reduction procedure well documented in the cephalosporin art. Generally, this procedure is carried out by first oxidizing the 2-cephem compound with, e.g., m-chloroperbenzoic acid, to give the corresponding 3-cephem 1-oxide derivative which is subsequently reduced via a trivalent phosphorous compound, such as phosphorous tribromide or phosphorous trichloride, preferably using dimethylformamide as a solvent.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([OH:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.Cl>O1CCCC1>[OH:14][C:8]1[CH:7]=[CH:6][C:5]([S:2]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)(=[O:4])=[O:3])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1O
Reactant: C1CCNC1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)c1cc(S(=O)(=O)N2CCCC2)ccc1O

Procedure:
A solution of 5-chlorosulfonyl-2-hydroxybenzoic acid (0.52 g, 2.0 mmol, Matrix Scientific) in tetrahydrofuran (10 mL) was treated with pyrrolidine (1.5 g, 21 mmol) and refluxed for 2 h. This was cooled and poured into dilute aqueous hydrochloric acid and extracted into dichloromethane (2×50 mL). The combined extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated to give a solid. This was triturated with ether to give 2-hydroxy-5-(pyrrolidine-1-sulfonyl)benzoic acid as a solid. It was then converted to 2-ethoxy-5-(pyrrolidine-1-sulfonyl)benzoic acid ethyl ester In a manner analogous to the method described in example 33.
Reaction SMILES: [Zn](CC)CC.[CH3:6][O:7][C:8](=[O:29])[N:9]([C@H:20]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[CH3:21])[CH2:10][CH2:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Br[CH2:31][C:32]([O:34][CH3:35])=[O:33].ClCCl>ClCCCl>[CH3:35][O:34][C:32](=[O:33])[CH2:31][C:12]([OH:19])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:11][CH2:10][N:9]([C@H:20]([C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1)[CH3:21])[C:8]([O:7][CH3:6])=[O:29]
Reactant: COC(=O)CBr
Reactant: COC(=O)N(CCC(=O)c1ccccc1)[C@@H](C)c1ccc(Cl)cc1
Agent: CC[Zn]CC
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)CC(O)(CCN(C(=O)OC)[C@@H](C)c1ccc(Cl)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Et2Zn (1 M in hexane, 55 mL) was added dropwise to [(S)-1-(4-chloro-phenyl)-ethyl]-(3-oxo-3-phenyl-propyl)-carbamic acid methyl ester (3.80 g) dissolved in 1,2-dichloroethane (30 mL) and chilled to 0° C. under argon atmosphere. Then, (Ph3P)3RhCl (0.50 g) was added followed by the dropwise addition of methyl bromoacetate (1.0 mL) dissolved in 1,2-dichloroethane (10 mL). The resulting solution was stirred at 0-5° C. for 1 h and at ambient temperature for another 1.5 h. The solution was poured into ice-cold half-saturated aqueous NH4Cl solution (150 mL). After addition of dichloromethane, the mixture was filtered through Celite that was extracted with an additional portion of dichloromethane. The organic phase was separated and washed with water and dried (MgSO4). The solvent was removed and the residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 85:15→70:30) to give the title compound as a mixture of two diastereomers.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[N:11]=[C:10]2[O:23][CH3:24])=[C:4]([F:25])[CH:3]=1.S(OC)(O[CH3:30])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[Cl:1][C:2]1[C:7]([O:8][CH3:30])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:21])([F:22])[C:17]([F:20])([F:18])[F:19])[N:11]=[C:10]2[O:23][CH3:24])=[C:4]([F:25])[CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: COc1nc(C(F)(F)C(F)(F)F)cc(=O)n1-c1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc(-n2c(OC)nc(C(F)(F)C(F)(F)F)cc2=O)c(F)cc1Cl

Procedure:
using 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-2-methoxy-4-pentafluoroethyl-6(1H)-pyrimidinone and dimethyl sulphate with sodium carbonate in acetone there is obtained 1-(4-chloro-2-fluoro-5-methoxyphenyl)-2-methoxy-4-pentafluoroethyl-6(1H)-pyrimidinone. m.p. 123°-125° C.;
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH2:13][O:12][CH2:11][CH2:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].ClC1C=CC=C(C(OO)=[O:22])C=1>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]2[CH2:13][O:12][CH2:11][CH2:10][C:7]2=[N+:8]([O-:22])[CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnc2c(c1)COCC2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc2c([n+]([O-])c1)CCOC2
Yield: 83.6 %

Procedure:
To a solution of 2.00 g of 3-nitro-7,8-dihydro-5H-pyrano[4,3-b]pyridine [prepared according to the method as described in Bull. Chem. Soc. Jpn. Vol. 63 (1990), 2820] in 40 ml of methylene chloride is added 2.63 g of m-chloroperbenzoic acid, and the resultant mixture is stirred overnight. The reaction mixture is washed with aqueous potassium carbonate, dried over anhydrous magnesium sulfate and the solvent is evaporated. The crude product is recrystallized from ethanol-chloroform to give 1.82 g of 3-nitro-7,8-dihydro-5H-pyrano[4,3-b]pyridine-1-oxide as colorless crystals. Yield: 84%. To a solution of 1.47 g of the product in 75 ml of methanol-dimethylformamide (1:1) is added 100 mg of 10% palladium carbon, and the resultant mixture is hydrogenated at ordinary temperature under atmospheric pressure. After the reduction is completed in about 3 hours, the catalyst is filtered off. The resultant crude crystals are washed with ethanol to give 1.08 g of 3-amino-1-oxide as colorless crystals. Yield: 86%. To a solution of 690 mg of 3-isoxazolylcarbonyl chloride in 20 ml of dimethylformamide is added 414 mg of pyridine under ice cooling, and then 830 mg of 3-amino-1-oxide as crystals is added. The resultant mixture is stirred under ice cooling for 30 minutes and at room temperature for 1 hour, chilled again with ice, and mixed with 4 ml of water. The suspension is neutralized with sodium bicarbonate. The precipitated solid is filtered, washed with water and ethanol in this order and dried to give 1.13 g of the titled compound as colorless crystals. Yield: 86%. ml.: 260° to 265° C. (dec.)
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([CH:20]([C:22]2[C:30]3[C:25](=[N:26][CH:27]=[C:28]([Cl:31])[CH:29]=3)[NH:24][CH:23]=2)O)=[C:14]([Cl:32])[CH:13]=1.C(#N)C.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>>[Cl:32][C:14]1[C:15]([CH2:20][C:22]2[C:30]3[C:25](=[N:26][CH:27]=[C:28]([Cl:31])[CH:29]=3)[NH:24][CH:23]=2)=[CH:16][C:17]([O:18][CH3:19])=[C:12]([CH:13]=1)[O:11][CH2:10][C:2]1[NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=1
Reactant: COc1cc(C(O)c2c[nH]c3ncc(Cl)cc23)c(Cl)cc1OCc1nc2ccccc2[nH]1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1cc(Cc2c[nH]c3ncc(Cl)cc23)c(Cl)cc1OCc1nc2ccccc2[nH]1
Temperature: 70 °C

Procedure:
[4-(1H-Benzoimidazol-2-ylmethoxy)-2-chloro-5-methoxy-phenyl]-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (138, 1.25 g, 0.00266 mol) was dissolved in acetonitrile (100 mL, 2 mol) and trifluoroacetic acid (5.65 mL, 0.0734 mol) and triethylsilane (11.3 mL, 0.0708 mol) were added. The reaction was heated at 70° C. for 2.5 hours. The reaction was concentrated and ethyl acetate and 1M aqueous potassium carbonate were added. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was adsorbed onto silica and purified with silica gel column chromatography, eluting with 0-8% methanol:dichloromethane to provide the desired compound as a solid, which was washed with a minimum of ethyl acetate and hexanes and filtered. The collected solid was dried to provide P-2104 (232 mg, 19%). MS (ESI) [M+H+]+=453.1, 455.1.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.ICCCC(O[C:19]([CH3:22])([CH3:21])[CH3:20])=O>C=C(C)C>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)CCCI
Agent: C=C(C)C
Product: CC(C)(C)OC(=O)c1ccc(CBr)cc1

Procedure:
4-(Bromomethyl)benzoic acid (6 g, 26 mmol) and isobutene (30 ml) were reacted by the same procedure as described in Example 3 for the preparation of tert-butyl 4-iodobutanoate and afforded the title material (2.4 g) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][PH:13](=[O:17])[O:14][CH2:15][CH3:16])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:18][Mg+].[Br-]>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][P:13]([CH3:18])(=[O:17])[O:14][CH2:15][CH3:16])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCO[PH](=O)COS(=O)(=O)c1ccc(C)cc1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOP(C)(=O)COS(=O)(=O)c1ccc(C)cc1
Yield: 77 %

Procedure:
To the crude ethyl (4-methylphenyl)sulfonyloxymethylphosphinate monochloridate (2.00 g, 6.39 mmol) in dry THF (30.0 mL) at −78° C. was added MeMgBr (2.20 mL, 6.97 mmol, 3.0 M in diethyl ether). The reaction was quenched immediately after the MeMgBr addition with 1 mL of acetic acid. The reaction mixture was diluted with ethyl acetate and H2O and the organic layer was washed twice with saturated aqueous NaHCO3 and once with H2O. The organic layer was concentrated and coevaporated with MeOH. The product was obtained by precipitation from hexanes to afford the title compound as a white solid (1.40 g, 77% over two steps): 1H NMR (200 MHz, DMSO-d6): δ 7.85 (m, 2H), 7.52 (m, 2H), 4.30 (d, J=12.0 Hz, 2H), 3.90 (m, 2H), 2.40 (s, 3H), 1.45 (d, J=21.0 Hz, 3H), 1.15 (m, 3H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-methanol (9:1); Rf=0.27.