Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[S:19][C:18]4[C:13](=[N:14][CH:15]=[CH:16][C:17]=4[O:20][C:21]4[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=4[F:28])[CH:12]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H][H]>[Pd].CO>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[S:19][C:18]4[C:13](=[N:14][CH:15]=[CH:16][C:17]=4[O:20][C:21]4[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=4[F:28])[CH:12]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: [H][H]
Reactant: Nc1ccc(Oc2ccnc3cc(C4=CCC5(CC4)OCCO5)sc23)c(F)c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(Oc2ccnc3cc(C4CCC5(CC4)OCCO5)sc23)c(F)c1
Temperature: 25 °C
Yield: 25.6 %

Procedure:
A round-bottomed flask was charged with 4-(2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluoroaniline (Example 161, Step A, 50.0 mg, 0.125 mmol), palladium on carbon (44.6 mg, 0.0376 mmol, 10%) and MeOH (10 mL). The air was exchanged with nitrogen three times and then was exchanged with hydrogen another three times. Then the reaction mixture was stirred under hydrogen at room temperature until the starting material had been consumed (overnight). The mixture was filtrated to remove the palladium on carbon and then the solvent was removed under reduced pressure to afford crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (12.8 mg, 25.5%). LRMS (APCI pos): m/e 401 (M+1). 1H NMR (400 MHz, CDCl3) δ 8.40 (m, 1H), 7.25 (s, 1H), 7.02 (t, 1H), 6.42-6.60 (m, 3H), 4.00 (s, 4H), 3.81 (br s, 2H), 2.89 (m, 1H), 2.14 (m, 2H), 1.90 (m, 4H), 1.72 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([Cl:13])[C:3]=1[C:4]#[N:5].[CH3:14][NH2:15].O.CCCCCC>CCOC(C)=O>[Cl:13][C:6]1[C:3]([C:4]#[N:5])=[C:2]([NH:15][CH3:14])[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=1
Reactant: N#Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: CN
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: CNc1c([N+](=O)[O-])ccc(Cl)c1C#N
Reaction time: 3 h
Yield: 83.4 %

Procedure:
A solution of 2,6-dichloro-3-nitrobenzonitrile (98.7 g, 0.455 mol) in EtOAc (910 mL) was cooled to 5° C. 40% Aqueous methylamine (79.5 mL, 1.14 mol) was added with vigorous mechanical stirring, keeping the temperature at 10-15° C. After addition was complete, stirring was continued for 3 h at the same temperature. More methylamine (16 mL, 0.23 mol) was added, and the mixture stirred for a further 1.5 h at room temperature. Water (300 mL) was added, followed by hexane (450 mL). The mixture was stirred for 15 min, filtered, and the solid washed with water and MeOH, to give 6-chloro-2-methylamino-3-nitrobenzonitrile (80.3 g, 83%), mp 167-170° C.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)=[O:5].[C:20](OC)(OC)(OC)[CH3:21]>C(O)C>[Cl:19][C:16]1[CH:15]=[C:3]2[C:2](=[CH:18][CH:17]=1)[N:1]=[C:20]([CH3:21])[N:6]([CH2:7][CH2:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)[C:4]2=[O:5]
Reactant: Nc1ccc(Cl)cc1C(=O)NCCCn1ccnc1
Reactant: COC(C)(OC)OC
Solvent: CCO
Product: Cc1nc2ccc(Cl)cc2c(=O)n1CCCn1ccnc1

Procedure:
A mixture of 2.79 g of 2-amino-5-chloro-N-[3-(1H-imidazol-1-yl)propyl]benzamide, 5 ml of trimethyl orthoacetate and 10 ml of ethyl alcohol was heated at reflux for 24 hours. The resulting solution was concentrated and the residue was triturated with ether and gave a solid. The ether was decanted and the solid was dissolved in ethyl acetate and allowed to stand. The precipitate was collected and gave 650 mg of the desired product as tan crystals, mp 190°-192° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:30][O:31][C:32]1[C:33](=[O:56])[C:34]([CH3:55])=[C:35]([CH2:41][C:42]2[CH:43]=[CH:44][C:45]([O:51][C:52](=[O:54])[CH3:53])=[C:46]([CH:50]=2)[C:47](O)=[O:48])[C:36](=[O:40])[C:37]=1[O:38][CH3:39]>C(Cl)Cl>[O:11]1[CH2:10][CH2:9][N:8]([C:3]2[C:2]([NH:1][C:47](=[O:48])[C:46]3[CH:50]=[C:42]([CH2:41][C:35]4[C:36](=[O:40])[C:37]([O:38][CH3:39])=[C:32]([O:31][CH3:30])[C:33](=[O:56])[C:34]=4[CH3:55])[CH:43]=[CH:44][C:45]=3[O:51][C:52](=[O:54])[CH3:53])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:13][CH2:12]1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: Nc1cccnc1N1CCOCC1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cccnc3N3CCOCC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 62 %

Procedure:
3-Amino-2-morpholinopyridine (0.269 g, 1.500 mmol), triethylamine (0.197 g, 1.950 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.165 g, 0.975 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.281 g, 0.750 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (ethyl acetate:hexane=2:1) to obtain the titled compound (0.249 g, 0.465 mmol, 62%).
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][CH:8]=1.II.C1(OC)C=CC=CC=1.C[O:22][B:23](OC)[O:24]C>C1COCC1.C(OCC)C>[CH3:10][O:9][C:5]1[CH:4]=[C:3]([B:23]([OH:24])[OH:22])[CH:8]=[CH:7][CH:6]=1
Reactant: COc1cccc(Br)c1
Reactant: COB(OC)OC
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: COc1ccccc1
Solvent: C1CCOC1
Product: COc1cccc(B(O)O)c1
Temperature: 65 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
Magnesium turnings (10.4 g, 428 mmol) were placed in a three-necked flask equipped with one condenser and one addition funnel and the flask was flame-dried under a stream of nitrogen. Rubber septa were used to enclose the vessel and the reaction was run under a stream of nitrogen. A solution of 3-bromoanisole (40 g, 214 mmol) in THF (400 mL) was placed in the addition funnel. The magnesium turnings were covered with THF and warmed to 65° C. A crystal of iodine and then a few mL of the anisole solution were added to the turnings. A few minutes later the amber color disappeared. The anisole solution was then slowly dripped into the reaction vessel. After all of the anisole was added, the reaction was maintained at 65° C. for 2 h. After cooling to ambient temperature, the Grignard solution was poured into a solution of trimethylborate (24.96 g, 240 mmol) in diethylether (250 mL) and stirred for 1 h. The solution was quenched with 1N HCl and extracted with ether. The ether was removed by rotary evaporation leaving the boronic acid as an white solid (27.59 g, 181.51 mmol).
Reaction SMILES: Cl[C:2]([S:4]Cl)=[O:3].[NH2:6]/[C:7](/[CH3:14])=[CH:8]\[C:9]([O:11][CH2:12][CH3:13])=[O:10]>C1(C)C=CC=CC=1>[CH3:14][C:7]1[NH:6][C:2](=[O:3])[S:4][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: O=C(Cl)SCl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1sc(=O)[nH]c1C
Yield: 62.4 %

Procedure:
25 g of chlorocarbonylsulphenyl chloride was added dropwise to 25 g of ethyl 3-aminocrotonate in 300 ml of toluene while being cooled with ice. The solution was heat-refluxed for 2 hours, and then cooled. The crystals precipitated were collected through filtration, and then washed twice with toluene to obtain 22.3 g of 4-methyl-5-ethoxycarbonyl-2-thiazolone as purple crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1C=CC=CC=1.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH:11][C:12]([OH:14])=[O:13]
Reactant: O=Cc1cccc(Cl)c1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cccc(Cl)c1

Procedure:
The starting material is prepared as follows: The mixture of 50 g of 3-chlorobenzaldehyde, 41 g of malonic acid and 36 ml of pyridine is heated on the steam bath for 3 hours. The residue is dissolved in 200 ml of water, the solution acidified with hydrochloric acid, filtered, and the residue recrystallized from aqueous ethanol, to yield the 3-chlorocinnamic acid melting at 150°-152°.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:14](Br)([CH3:16])[CH3:15]>>[CH3:15][CH:14]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH3:16]
Reactant: CC(C)Br
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Product: CC(C)n1c2ccccc2c2ccccc21

Procedure:
Carbazole (5 g; 0.03 mol) was reacted with isopropyl bromide (5.61 ml; 0.06 mol) by working in a manner similar to that described in Example 1a).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:10]([CH:11]=[O:12])=[C:4]2[CH:3]=1.[C:21]([Mg]Br)#[CH:22]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:10]([CH:11]([OH:12])[C:21]#[CH:22])=[C:4]2[CH:3]=1
Reactant: C#C[Mg]Br
Reactant: COc1ccc(-c2nn3ccc(Cl)cc3c2C=O)cc1
Solvent: C1CCOC1
Product: C#CC(O)c1c(-c2ccc(OC)cc2)nn2ccc(Cl)cc12
Yield: 106.9 %

Procedure:
5-Chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (0.90 g, 3.14 mmol) in tetrahydrofuran (50 mL) was treated with ethynylmagnesium bromide (7.5 mL, 0.5 M in tetrahydrofuran, 3.77 mmol) as described in Example 12 to give 1-[5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol (1.05 g, 100%) as a white solid. 1H NMR (CDCl3) δ 8.40 (d, 1H), 8.05 (s, 1H), 7.72 (d, 2H), 7.05 (d, 2H), 6.80 (dd, 1H), 5.78 (s, 1H), 3.91 (s, 3H), 2.74 (s, 1H), 2.53 (s, 1H); MS m/z 313 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]=[O:13])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:31]([O:30][CH2:29][CH2:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH:12]=[O:13])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:26][CH:25]=1)[CH2:32][CH2:33][CH3:34]
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(C=O)CC1
Reactant: CCCCOCCOc1ccc(OB([O-])[O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
A mixture of methyl 7-bromo-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.25 g), 4-(2-butoxyethoxy)phenyl borate (0.23 g), 1M potassium carbonate solution (2.5 ml), ethanol (2.5 ml) and toluene (25 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.04 g), and the mixture was refluxed overnight under argon atmosphere and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-formyl-2.3-dihydro-1H-1-benzazepine-4-carboxylate (0.23 g) as colorless oil.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl:16][S:17](O)(=[O:19])=[O:18]>C(OCC)C>[CH2:1]([C:9]1[C:10]([CH3:15])=[C:11]([S:17]([Cl:16])(=[O:19])=[O:18])[CH:12]=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=S(=O)(O)Cl
Reactant: CCCCCCCCc1ccccc1C
Solvent: CCOCC
Product: CCCCCCCCc1cccc(S(=O)(=O)Cl)c1C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Octyltoluene (50 g.-0.245 mole) as prepared in Table 1 was added slowly at 5°-10° C. with stirring over one half hour (some exotherm) to 81 g. (0.69 mole) chlorosulfonic acid in a 250 ml. round bottom flask fitted with air stirrer, thermometer, addition funnel, reflux condenser, scrubber and ice bath. The reaction mixture was allowed to stir for three hours at 25°-30° C. and then stand overnight. It was poured onto 900 g. ice, 500 ml. diethyl ether was added and the mixture was stirred until the ice melted. The resulting organic phase was washed with water, 30% aqueous Na2CO3, again with water, dried over Na2SO4 and the solvent was evaporated. Thirty nine g. of octylmethylbenzenesulfonyl chloride was obtained.
Reaction SMILES: [C:1]([C:5]1[C:10](O)=[C:9]([CH3:12])[C:8]([CH3:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[ClH:14].S(=O)(=O)(O)O.COC[O:23][CH3:24]>C1(C)C=CC=CC=1>[C:1]([C:5]1[C:24]([OH:23])=[C:7]([CH3:6])[C:8]([CH3:13])=[C:9]([CH:10]=1)[CH2:12][Cl:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(C)(C)C)c(O)c1C
Reactant: Cl
Reactant: COCOC
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Cc1c(CCl)cc(C(C)(C)C)c(O)c1C

Procedure:
30 grams of 6-tert.-butyl-2,3-dimethylphenol dissolved in 100 ml of toluene was added to 2.7 ml of concentrated hydrochloric acid containing 3.3 ml of concentrated sulfuric acid at 5° to 10°C. 26 grams of methylal was added dropwise to the above vigorously stirred dispersion over a period of about 15 minutes. After this the reaction mixture was heated at 36° to 37° for 2 hours while bubbling anhydrous gaseous hydrogen chloride through the reaction mixture. The reaction temperature was allowed to drop to 27° during the following 2 hours while continuing to bubble anhydrous hydrogen chloride through the reaction mixture. The acidic aqueous phase was separated from the reaction mixture after being extracted with toluene. The combined toluene phases were washed well with cold water and dried over anhydrous sodium sulfate. After filtering free of drying agent, the clear filtrate was freed of solvent by distillation at reduced pressures the resulting residue being crystallized from petroleum ether yielding the desired compound in the form of light yellow crystals melting at 92° to 95°C.
Reaction SMILES: Cl.[CH2:2]([N:9]([CH2:16][C:17]([C:19]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:24]2[C:20]=1[CH:21]=[C:22]([C:36]([OH:38])=[O:37])[NH:23]2)=[O:18])[CH:10]([CH3:15])[CH2:11][C:12]([OH:14])=[O:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:40][O:41][CH3:42].[O:43]1[CH2:48]COC[CH2:44]1.C(O)(=O)C>>[C:12]([OH:14])(=[O:13])[CH3:11].[CH3:40][O:41][CH2:42][O:37][C:36]([C:22]1[NH:23][C:24]2[C:20]([CH:21]=1)=[C:19]([C:17](=[O:18])[CH2:16][N:9]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH:10]([CH3:15])[CH2:11][C:12]([O:14][CH2:44][O:43][CH3:48])=[O:13])[CH:27]=[CH:26][C:25]=2[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:38]
Reactant: CC(CC(=O)O)N(CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(C(=O)O)cc12)Cc1ccccc1
Reactant: C1COCCO1
Reactant: COCCl
Agent: Cl
Solvent: CC(=O)O
Product: COCOC(=O)CC(C)N(CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(C(=O)OCOC)cc12)Cc1ccccc1

Procedure:
Under the conditions of Example 21(A), 5 g of 4-[N-benzyl-N-(2-carboxy-1-methylethyl)aminoacetyl]-7-benzyloxyindole-2-carboxylic acid hydrochloride is reacted with 1.6 g of chloromethylmethyl ether and worked up. Treatment of the crude product with dioxane/acetic acid yields 4.2 g of 4-[N-benzyl-N-(2-methoxymethoxycarbonyl-1-methylethyl)aminoacetyl]-7-benzyloxyindole-2-carboxylic acid methoxymethyl ester acetate, decomposition point 118°-122° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]1[CH2:11][O:10][CH2:9][CH2:8]1.[OH2:12]>C1COCC1.C1C=CC=CC=1>[OH:10][CH2:11][C@H:7]1[C@@H:8]([CH2:9][OH:12])[CH2:9][CH:8]=[CH:7][CH2:11]1
Reactant: O
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: c1ccccc1
Product: OC[C@@H]1CC=CC[C@@H]1CO
Temperature: 0 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
(25.8 g) in THF (150 ml) is added with cooling to a stirred suspension of LiAlH4 (9 g) in THF (200 ml) under N2 at a rate such as to maintain the temperature at 0° C. After stirring for 18 hours at room temperature the mixture is gently refluxed for one hour and cooled in ice. The excess lithium aluminium hydride is decomposed by the careful addition of 1:1 THF-H2O mixture (100 ml). After dilution with chloroform (150 ml) the resulting mixture is filtered and the solid is washed with chloroform (3×25 ml). Concentration of the filtrate under reduced pressure yields an oily residue which is dissolved in benzene, dried over (MgSO4) and reconcentrated in vacuo to give the title compound as an oil (22 g, ca. 90%), νmax (film) 3350 cm-1.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[C:4]([OH:16])[CH:3]=1.C(N(CC)CC)C.[P:24](=[O:32])(Cl)([S:27][CH2:28][CH2:29][CH3:30])[O:25][CH3:26].C(OCC)(=O)C>C1(C)C=CC=CC=1>[P:24](=[O:32])([S:27][CH2:28][CH2:29][CH3:30])([O:16][C:4]1[CH:3]=[C:2]([Cl:1])[C:15]2[C:6](=[CH:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=1)[O:25][CH3:26]
Reactant: CCCSP(=O)(Cl)OC
Reactant: Oc1cc(Cl)c2cc3ccccc3cc2c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCSP(=O)(OC)Oc1cc(Cl)c2cc3ccccc3cc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Chloro-2-anthrol (0.01 mole), triethylamine (0.01 mole) tetrahydrofuran (25 ml) and toluene (25 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture is cooled to a temperature of about 0° C. and O-methyl S-propyl phosphorochloridothioate (0.01 mole) dissolved in toluene (25 ml) is added with stirring over a period of about 30 minutes. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 16 hours. After this time the reaction mixture is filtered to remove triethylamine hydrochloride. The filtrate is then washed with water, dried over anhydrous magnesium sulfate and stripped of solvents leaving a residue. This residue is subjected to flash chromatography using ethyl acetate as the eluant to yield the desired product O-methyl O-(4-chloro-2-anthryl) S-propyl phosphorothioate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:14](Br)[C:15]#[CH:16].N1C(C)=CC=CC=1C>CN(C)C(=O)C>[CH3:12][N:11]([CH3:13])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH2:16][C:15]#[CH:14])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: C#CCBr
Reactant: CN(C)S(=O)(=O)c1ccc(N)cc1
Solvent: Cc1cccc(C)n1
Solvent: CC(=O)N(C)C
Product: C#CCNc1ccc(S(=O)(=O)N(C)C)cc1
Yield: 602.3 %

Procedure:
Under an atmosphere of nitrogen gas, a mixture of 17 g (0.0085 mol) of 4-amino-N,N-dimethylbenzenesulfonamide, 25.5 ml (0.229 mol) of propargyl bromide, and 20.4 ml (0.175 mol) of 2,6-lutidine in 250 ml of N,N-dimethylacetamide is stirred at 90° for three and one-half hours, allowed to cool, and concentrated in vacuo. The concentrate is taken up in dichloromethane and water; the organic layer is separated, washed with brine, dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue is chromatographed over 1.1 kg of silica gel with a gradient of ethyl acetate in toluene of 10 to 15% to give 12.2 g of product, Rf (10% methanol/dichloromethane)≃0.84. Recrystallization from ethanol affords 10.2 g (50%) of product, as off-white crystals; mp 128°-131° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][NH:4][N:3]=1.S(=O)(=O)(O)O.C([O-])(O)=O.[Na+].[CH2:20](O)[CH3:21]>>[CH3:1][C:2]1[C:6]([C:7]([O:9][CH2:20][CH3:21])=[O:8])=[CH:5][NH:4][N:3]=1
Reactant: CCO
Reactant: Cc1n[nH]cc1C(=O)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1c[nH]nc1C
Temperature: 25 °C
Yield: 58 %

Procedure:
To a solution of 3-methyl-1H-pyrazole-4-carboxylic acid (2.986 g, 23.68 mmol) in ethanol (20 ml) was added concentrated sulphuric acid (1 ml). The reaction was heated at reflux for 6 hours, cooled to room temperature, and then poured into a saturated aqueous solution of NaHCO3. The mixture was extracted with dichloromethane (3×50 ml) then the combined organic extracts dried over MgSO4 and concentrated in vacuo. The product crystallised on standing (2.105 g, 58% yield).
Reaction SMILES: [N+](=[C:3]([C:17](=[O:28])[C@@H:18]([C@@H:20]1[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[NH:21]1)[CH3:19])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])=[N-]>ClC(Cl)C.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[OH:26][C@@H:24]([C@H:23]1[C:22](=[O:27])[N:21]2[C@@H:20]1[C@@H:18]([CH3:19])[C:17](=[O:28])[CH:3]2[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])[CH3:25]
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: CC(Cl)Cl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12

Procedure:
To a solution of 4-nitrobenzyl (4R)-2-diazo-4-[(2R,3S)-3-{(1R)-1-hydroxyethyl}-4-oxoazetidin-2-yl]-3-oxopentanoate (0.35 g) in dichloroethane (10 ml) was added rhodium acetate (1 mg) under reflux in a nitrogen stream. The mixture was refluxed for 30 minutes and concentrated under reduced pressure to give 4-nitrobenzyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate. The compound obtained above was dissolved in acetonitrile (10 ml). To the solution was added diphenyl phosphorochloridate (0.20 ml) at -10°~-5° C. in nitrogen stream and dropwise added N,N-diisopropyl-N-ethylamine (0.20 ml) at the same condition. The mixture was stirred at the same condition for 1 hour. To the solution were added N,N-diisopropyl-N-ethylamine (0.2 ml) and then a solution of (2S,4S)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)-2-[2-(4-nitrobenzyloxycarbonylamino)ethyloxymethyl] pyrrolidine (0.46 g) in acetonitrile (2 ml) at -20° C. The mixture was stirred at the same temperature for 30 minutes and then at 0°-10° C. for 3 hours. The mixture was poured into a mixture of water (60 ml) and ethyl acetate (90 ml). The organic layer was washed with water (90 ml×2) and brine (90 ml) successively, dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with a mixture of acetone and dichloromethane (5:95, 10:90, and 15:85, in turn) to give 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[(2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-{2-(4-nitrobenzyloxycarbonylamino)ethyloxymethyl}pyrrolidin-4-yl]thio-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.45 g).