Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[H-].[Na+].[CH3:18]I.[Cl-].[NH4+]>CN(C=O)C>[CH3:18][NH:6][C:5]1[CH:7]=[CH:8][C:9]([O:11][C:12]([F:13])([F:14])[F:15])=[CH:10][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: Nc1ccc(OC(F)(F)F)cc1[N+](=O)[O-]
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CNc1ccc(OC(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 76.3 %

Procedure:
To a mixture of 2.22 g of 2-nitro-4-trifluoromethoxyaniline and 20 ml of DMF was added 0.44 g of sodium hydride (60% oily), and the mixture was stirred for 10 minutes under ice cool. To this mixture was added 1.42 g of methyl iodide, then, the mixture was stirred for 1 hour at room temperature. Into the reaction mixture, a saturated ammonium chloride aqueous solution was poured, and the mixture was extracted three times with ethyl acetate. The organic layer was dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.80 g of N-methyl-2-nitro-4-trifluoromethoxyaniline.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].Br[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C)C=O>[CH2:10]([N:4]1[CH:3]=[C:2]([I:1])[CH:6]=[N:5]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Ic1cn[nH]c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Ic1cnn(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
A 250-mL round-bottomed flask was charged with 4-iodo-1H-pyrazole (17 g, 87.63 mmol, 1.00 equiv) in N,N-dimethylformamide (150 mL) To this was added sodium hydride (3.6 g, 105.00 mmol, 1.20 equiv, 70%) in several batches at 0° C., followed by addition of 1-(bromomethyl)benzene (16.5 g, 96.49 mmol, 1.10 equiv) dropwise at 0° C. The resulting solution was allowed to warm up to room temperature and stirred for 2 hours at room temperature. The reaction was then quenched by the addition of water/ice (200 mL). The resulting solution was extracted with ethyl acetate (3×200 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered off and concentrated on a rotary evaporator affording 1-benzyl-4-iodo-1H-pyrazole as yellow solid (22 g, 80%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)[C:5]=1[OH:24].BrC1C=CC=CC=1O.[CH2:34]([N:36]([CH2:49][CH3:50])[C:37](=[O:48])[C:38]1[CH:43]=[CH:42][C:41](F)=[C:40]([N+]([O-])=O)[CH:39]=1)[CH3:35].FC1C=C(C=CC=1[N+]([O-])=O)C#N>>[CH3:1][O:2][C:3]([C:4]1[C:5]2[O:24][C:42]3[C:41](=[CH:40][CH:39]=[C:38]([C:37](=[O:48])[N:36]([CH2:49][CH3:50])[CH2:34][CH3:35])[CH:43]=3)[N:10]([CH:11]3[CH2:12][CH2:13][N:14]([CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:15][CH2:16]3)[C:6]=2[CH:7]=[CH:8][CH:9]=1)=[O:25]
Reactant: CCN(CC)C(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: COC(=O)c1cccc(NC2CCN(Cc3ccccc3)CC2)c1O
Agent: N#Cc1ccc([N+](=O)[O-])c(F)c1
Agent: Oc1ccccc1Br
Product: CCN(CC)C(=O)c1ccc2c(c1)Oc1c(C(=O)OC)cccc1N2C1CCN(Cc2ccccc2)CC1

Procedure:
Using an adaptation of the method described in Procedure 1, substituting 3-(1-benzylpiperidin-4-ylamino)-2-hydroxybenzoic acid methyl ester, 2l for 2-bromophenol, and N,N-diethyl-4-fluoro-3-nitrobenzamide for 3-fluoro-4-nitrobenzonitrile, the title compound 10-(1-benzylpiperidin-4-yl)-7-diethylcarbamoyl-10H-phenoxazine-4-carboxylic acid methyl ester, 3l was obtained.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[C:2]#[CH:3].[CH2:6](Br)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[C:2]#[CH:3]
Reactant: BrCc1ccccc1
Reactant: C#CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C#CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 37 %

Procedure:
To a solution of 17.0 g (233 mmol) of propiolic acid in 600 mL of anhydrous DMF was added 39.9 g (233 mmol) of benzyl bromide followed by portionwise addition of 76.0 g (233 mmol) of Cs2CO3. After stirring at room temperature for 24 h, the reaction was quenched with a saturated aqueous ammonium chloride solution and extracted with EtOAc (3×200 mL). The combined extracts were washed with water then brine and dried over anhydrous sodium sulfate. The mixture was then filtered through a silica gel pad washing with hexanes, and the filtrate was evaporated under reduced pressure to afford a crude product. The crude product was purified by silica gel chromatography eluting with a 0-20% ethyl acetate in hexane gradient to afford the title compound as a colorless oil (13.8 g, 35%). 1H NMR (CDCl3, 500 MHz) δ 7.41 (m, 5H), 5.25 (s, 2H), 2.92 (s, 1H).
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30]([NH:33][C:34]2[S:35][CH:36]=[CH:37][N:38]=2)(=[O:32])=[O:31])[C:20]1=[O:39])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[OH:18][CH:19]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30]([NH:33][C:34]2[S:35][CH:36]=[CH:37][N:38]=2)(=[O:31])=[O:32])[C:20]1=[O:39]
Reactant: CC(C)(C)[Si](OC1CCN(c2ccccc2S(=O)(=O)Nc2nccs2)C1=O)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O=C1C(O)CCN1c1ccccc1S(=O)(=O)Nc1nccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
To a solution of (R)-4-(3-(tert-butyldiphenylsilyloxy)-2-oxopyrrolidin-1-yl-N-(thiazol-2-yl)benzenesulfonamide (5.5 gm, 9.53 mmol) in THF (40 mL) under N2, was added a solution of tetrabutyl ammonium fluoride in THF (1M, 40 mL, 38.12 mmol). Upon completion of addition, the mixture was stirred at RT overnight. The reaction mixture was poured into water and extracted with CH2Cl2 (2×50 mL), dried over magnesium sulfate, and concentrated. Purification via silica gel chromatography using 2-10% MeOH in CH2Cl2 gave (R)-4-(3-hydroxy-2-oxopyrrolidin-1-yl-N-(thiazol-2-yl)benzenesulfonamide (2.6 gm, 76%). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=340.0; tR=0.54 min.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=2)[C:6]([C:20]([O:22]CC)=[O:21])=[CH:5][N:4]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O>CS(C)=O>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=2)[C:6]([C:20]([OH:22])=[O:21])=[CH:5][N:4]=1
Reactant: CCOC(=O)c1cnc(SC)nc1NCc1ccc(OC)c(Cl)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CNc2nc(SC)ncc2C(=O)O)cc1Cl
Temperature: 25 °C

Procedure:
2-Methylthio-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine (prepared in Example 67-(1)) 2.00 g is suspended in dimethyl sulfoxide 10 ml, and the suspension is treated with a 10% aqueous sodium hydroxide solution 10 ml. The reaction mixture is still in suspension even 6 hours later. After addition of dimethyl sulfoxide 5 ml the mixture is stirred at room temperature over night. The resulting clear reaction solution is acidified with citric acid. The excess water (about 50 ml) is added thereto and resulting precipitate is filtered, washed with isopropylalcohol and then isopropyl ether, and concentrated in vacuo to give 2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-carboxypyrimidine as a pale yellow impalpable powder, 1.864 g. mp 238–240° C. (decomposition)
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:25](Cl)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C.ClCCl>CO>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH:21]([OH:24])[CH2:22][O:23][C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCC(O)COCCCCCCCCCCCCC1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: OC(COCCCCCCCCCCCCC1CCCCC1)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 129.6 %

Procedure:
A mixture of 23.5 g (68.6 mmole) of 1-(12-cyclohexyldodecyloxy)-2,3-propanediol, 28.7 g (103 mmole) of trityl chloride, 13.7 g (137 mmole) of triethylamine and 200 ml of dichloromethane was stirred at room temperature for 2 days. To the reaction mixture was added 10 ml of methanol and the resulting mixture was further stirred for 3 hours. The mixture was washed with water and dried (MgSO4) and the solvent was distilled off to give 52 g (quantitative) of crude 1-(12-cyclohexyldodecyloxy)-3-trityloxy-2-propanol. In 100 ml of tetrahydrofuran (THF) was dissolved 17 g (23 mmole) of this product, and 1.84 g (46 mmole) of 60% sodium hydride was added thereto. The mixture was stirred at room temperature for 1 hour and 4 ml of methyl iodide was added to the mixture. The reaction mixture was stirred at room temperature overnight and then 5 ml of methanol was added thereto. The solvent was distilled off under reduced pressure, and the residue was dissolved in 200 ml of hexane and washed with water and 1N hydrochloric acid, in order. After hexane was distilled off, 30 ml of 1N hydrochloric acid and 60 ml of dioxane were added to the residue, and the mixture was stirred at 80° C. for 10 hours. The mixture was neutralized with sodium bicarbonate and then 60 ml of ethyl acetate was added to the mixture. The resulting mixture was washed with water and dried (MgSO4), and the solvent was distilled off. The residue was subjected to column chromatography on silica gel (200 g) and eluted with dichloromethane-ethyl acetate (5:1) to give 6.6 g (yield: 81%) of the above-mentioned compound as colorless solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[C:7]([CH2:24][CH2:25][CH3:26])=[N:6][N:5]=1.[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH3:1][O:2][CH2:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:29][N:28]=[N:27][N:23]=3)=[CH:12][CH:11]=2)[C:7]([CH2:24][CH2:25][CH3:26])=[N:6][N:5]=1
Reactant: CCCc1nnc(COC)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nnc(COC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 48 h
Yield: 20.8 %

Procedure:
To a solution of 3-methoxymethyl-5-propyl-4-[(2'-cyanobiphenyl-4-yl)methyl]-1,2,4-triazole (1.5 g, 4.33 mmol) in DMF (35 ml) was added sodium azide (NaN3, 0.84 g, 13 mmol) and ammonium chloride (NH4Cl, 0.69 g, 13 mmol). The mixture was stirred at 100° C. for four days whereupon an additional 0.3 g NaN3 and 0.23 g NH4Cl were added. Stirring was continued 2 days further at 100° C. The solvent was removed (rotary evaporation) and the residue was partitioned between ethyl acetate and water (100 ml ea). The organic phase was dried (MgSO4), filtered and concentrated to a viscous light brown oil (1.5 g) which was purified by flash chromatography on silica gel to give 350 mg (21%) of an off-white solid; m.p. 201°-205° C. (dec.).
Reaction SMILES: [N+](C1C=CC(C([O:10][C@H:11]2[CH2:14][C@H:13]([CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)=O)=CC=1)([O-])=O.[OH-].[Na+]>O1CCCC1>[OH:10][C@H:11]1[CH2:14][C@H:13]([CH2:15][NH:16][C:17](=[O:18])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:12]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1C[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC[C@H]1C[C@H](O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
To a solution in tetrahydrofuran (100 mL) of the compound (3.88 g) obtained in step (1) above, an aqueous solution of 1 mol/L sodium hydroxide (19.9 mL) was added and the mixture was stirred at room temperature for 4 hours. Extraction was conducted with ethyl acetate and after drying the combined organic layers over anhydrous magnesium sulfate, the desiccant was removed by filtration. With the solvent being distilled off under reduced pressure, the crude product was adsorbed on diatomaceous earth. The crude product as adsorbed on the diatomaceous earth was purified by silica gel column chromatography (n-hexane:ethyl acetate=99:1-0:100, then chloroform:methanol=100:0-90:10) to give tert-butyl [(trans-3-hydroxycyclobutyl)methyl]carbamate as a colorless solid (1.87 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][N:20]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:21][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[C:9]=2[C:10]=1[CH3:11])=[O:5])C.[OH-].[Li+].Cl.C(OCC)(=O)C>O1CCCC1.O>[C:31]([O:30][C:28]([N:20]([CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[CH2:19][CH2:18][CH2:17][O:16][C:12]1[C:9]2[C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[O:7][C:8]=2[CH:15]=[CH:14][CH:13]=1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: CCOC(=O)c1oc2cccc(OCCCN(Cc3cccnc3)C(=O)OC(C)(C)C)c2c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)oc2cccc(OCCCN(Cc3cccnc3)C(=O)OC(C)(C)C)c12
Yield: 96.5 %

Procedure:
4-[3-(tert-Butoxycarbonyl-pyridin-3-ylmethyl-amino)-propoxy]-3-methyl-benzofuran-2-carboxylic acid ethyl ester (634 mg), the first intermediate of Example 87, was stirred with lithium hydroxide (113 mg) in tetrahydrofuran (2.7 ml) and water (2.7 ml) at 50° C. overnight. 2N HCl (1.35 ml) and ethyl acetate were added to the reaction mixture. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was obtained as a colorless foam (575 mg, 97%). The foam was used as a starting material in the next step without further purification. ESI-MS: m/z 441 (MH+); 1H-NMR δ: 1.51 (9H, s), 2.05-2.11 (2H, m), 2.74 (3H, s), 3.44 (2H, m), 4.02 (2H, t, J=5.4 Hz), 4,51 (2H, s), 6.51 (1H, d, J=7.6 Hz), 7.14 (1H, d, J=8.3 Hz), 7.23-7.34 (2H, m), 7.79 (1H, br), 8.51 (1H, dd, J=1.3, 5.0 Hz), 8.59 (1H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].O(CC)[C:11]([S-])=[S:12].[K+].Cl>N1C=CC=CC=1>[CH3:9][C:5]1[CH:4]=[CH:3][C:2]2[NH:1][C:11](=[S:12])[O:8][C:7]=2[CH:6]=1
Reactant: CCOC(=S)[S-]
Reactant: Cc1ccc(N)c(O)c1
Agent: Cl
Agent: [K+]
Solvent: c1ccncc1
Product: Cc1ccc2[nH]c(=S)oc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6-amino-m-cresol (593.7 mg, 4.82 mmol) and potassium O-ethyl xanthate (850 mg, 5.30 mmol) in pyridine (10 mL) was stirred and heated to reflux for 2 h. It was cooled to rt, poured into a mixture of ice-water (40 mL), and concentrated HCl (4 mL). The solid was collected, washed with water, and dried in the hood overnight and then in a vacuum oven at 45° C. for 3 h. The product 6-methyl-1,3-benzoxazole-2(3H)-thione was obtained as beige powder (735 mg, yield 92.3%). 1H NMR (300 MHz, DMSO-d6) δ 7.10 (s, 1 H), 7.03 (d, 2 H), 2.42 (s, 3H); LC-MS ret. time 2.37 min (method 2), m/z 166.0 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([CH3:10])[CH:3]=1.C(N(CC)CC)C.Cl[Si:19]([CH3:22])([CH3:21])[CH3:20].O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:19]([CH3:22])([CH3:21])[CH3:20])=[C:4]([CH3:10])[CH:3]=1
Reactant: C[Si](C)(C)Cl
Reactant: Cc1cc(Br)ccc1CO
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(Br)ccc1CO[Si](C)(C)C
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of (4-bromo-2-methyl-phenyl)-methanol (Intermediate 133, 500.0 mg, 2.48 mmols), in 10 mL THF was added triethylamine (374.0 mg, 3.70 mmols) and chlorotrimethylsilane (297.0 mg, 2.70 mmols). The resulting solution was stirred for 17 hours at 25° C. and then treated with H2O and extracted with Et2O. The combined organic layers were washed with H2O, 10% aqueous HCl, saturated NaHCO3, and saturated NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound, 550.0 mg (81%), was isolated by column chromatography (5% EtOAc-hexanes) as a colorless oil.
Reaction SMILES: C1CCC=CCCC=1.O=O.[C-:11]#[N:12].[Na+].[NH2:14][C:15]1[C:24]([CH3:25])=[CH:23][C:22](Br)=[CH:21][C:16]=1[C:17]([NH:19][CH3:20])=[O:18]>Cl[Ni]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Zn]>[NH2:14][C:15]1[C:24]([CH3:25])=[CH:23][C:22]([C:11]#[N:12])=[CH:21][C:16]=1[C:17]([NH:19][CH3:20])=[O:18]
Reactant: [C-]#N
Reactant: CNC(=O)c1cc(Br)cc(C)c1N
Agent: Cl[Ni]Cl
Agent: [Fe+2]
Agent: O=O
Solvent: C1=CCCC=CCC1
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A reaction flask was charged with of [1,1′-bis(diphenylphosphino)ferrocene]-dichloronickel (68 mg, 0.099 mmol), zinc (130 mg, 1.99 mmol), 1,5-cyclooctadiene (28.3 mg, 0.262 mmol) and oxygen-free acetonitrile (4 mL) under a nitrogen atmosphere in a glovebox. After stirring for 2 h at room temperature, sodium cyanide (0.55 g, 11.22 mmol, ground prior to use), 2-amino-5-bromo-N,3-dimethylbenzamide (prepared by the method of Reference Example 1) (2.43 g, 9.99 mmol) and more oxygen-free acetonitrile (8 mL) were added to the reaction mixture. The flask was removed from the glovebox while maintaining a nitrogen atmosphere, and the reaction mixture was then heated at reflux (about 82° C.) while being vigorously stirred. After about 2 h and 25 minutes, HPLC analysis of the reaction mixture indicated about 96% conversion of the 2-amino-5-bromo-N,3-dimethylbenzamide with 2-amino-5-cyano-N,3-dimethylbenzamide being the major product. A portion of the reaction mixture (0.05 mL) was withdrawn and evaporated to dryness to give an analytical sample for 1H NMR analysis.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:3]=1.Br[C:13]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:8]([C:4]1[CH:3]=[C:2]([NH:1][C:13]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])[N:6]([CH3:7])[N:5]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: Cn1nc(C(C)(C)C)cc1N
Reactant: COC(=O)c1cc(OC)ccc1Br
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(OC)ccc1Nc1cc(C(C)(C)C)nn1C
Temperature: 110 °C
Reaction time: 16 h
Yield: 38.7 %

Procedure:
To a 100 mL oven dried flask, was added 5-amino-3-tert-butyl-1-methylpyrazole (2.00 g. 13.1 mmol), methyl 2-bromo-5-methoxybenzoate (2.67 g, 10.9 mmol), cesium carbonate (4.96 g, 15.2 mmol), Pd2(dba)3 (337 mg, 0.33 mmol), BINAP (338 mg, 0.54 mmol), and toluene (35 mL). The reaction mixture was degassed, placed under an N2 atmosphere, and then stirred at 110° C. for 16 h. The reaction mixture was cooled to rt, and ethyl acetate (30 mL) was added. The mixture was filtered, the filter cake washed with EtOAc (10 mL), and the filtrate concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (eluent: 10 to 30% EtOAc in hexane) to give the title compound as a light yellow oil (1.34 g, 38%). 1H NMR (400 MHz, CDCl3) δ 1.28 (s, 9H), 3.63 (s, 3H), 3.78 (s, 3H), 3.94 (s, 3H), 5.97 (s, 1H), 6.82 (d, 1H), 7.10 (dd, 1H), 7.47 (d, 1H).
Reaction SMILES: Cl[C:2]1[C:11]([O:12][CH2:13][CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:22]([O-:24])=[O:23].C(=O)([O-])[O-].[K+].[K+].[C:31]1([O:38][CH3:39])[C:32](=[CH:34][CH:35]=[CH:36][CH:37]=1)[OH:33]>CC(C)=O>[CH3:39][O:38][C:31]1[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=1[O:33][C:2]1[C:11]([O:12][CH2:13][CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:22]([O-:24])=[O:23]
Reactant: COC(=O)c1cc(OCCOC2CCCCO2)c(Cl)c([N+](=O)[O-])c1
Reactant: COc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(OCCOC2CCCCO2)c(Oc2ccccc2OC)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
4.28 g of methyl 4-chloro-3-nitro-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate were dissolved in acetone (250 ml), treated at RT with 5.0 g of potassium carbonate, 1.93 of guaiacol and the mixture was heated at reflux for 20 hours. It was poured on to ice-water and extracted with ethyl acetate. The organic phase was washed 3 times with 5% sodium hydroxide solution, then with water, dried over sodium sulphate and finally concentrated on a rotary evaporator. The crude product (6 g) was flash chromatographed on silica gel with hexane/ether (1/1). here was thus obtained the desired methyl 4-(2-methoxy-phenoxy)-3-nitro-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate as a pale yellow powder.
Reaction SMILES: [N+](C(C)C)([O-])=[O:2].[Na].Br[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:24]=[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]3[N:17]=2)=[CH:12][CH:11]=1>C(O)C.CN(C)C=O>[CH:9]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:24]=[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]3[N:17]=2)=[CH:12][CH:11]=1)=[O:2]
Reactant: CC(C)[N+](=O)[O-]
Reactant: BrCc1ccc(-c2nc3ccccn3n2)cc1
Agent: [Na]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=Cc1ccc(-c2nc3ccccn3n2)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
11.6 g of 2-nitropropane are introduced at about 30° C. into a solution of 2.3 g of sodium in 450 ml of absolute ethanol. The mixture is stirred for a further 1 hour and a solution of 28.8 g of 2-(p-bromomethyl-phenyl)-s-triazolo[1,5-a]pyridine (I) in 290 ml of dimethylformamide is now added. Subsequently, the reaction mixture is warmed to 50° C., then stirred for 20 hours without external warming and finally cooled to -10° C. The product which has precipitated is filtered off, washed with cold methanol and dried. This gives 19.3 g (86.5% of theory) of compound (II) in the form of a pale yellow powder with a melting point of 243° to 244° C. After recrystallising twice from dimethylformamide, 14.67 g (65.7% of theory) of small, virtually colourless, glossy needles with a melting point of 246° to 247° C. are obtained.
Reaction SMILES: [OH-].[Na+].C(#N)C.[CH3:6][CH2:7][C@@H:8]([C:10]([O:12][C@@H:13]1[C@@H:18]2[C@@H:19]([CH2:24][CH2:25][C@@H:26]([OH:34])[CH2:27][C@@H:28]([OH:33])[CH2:29][C:30]([O-:32])=[O:31])[C@@H:20]([CH3:23])[CH:21]=[CH:22][C:17]2=[CH:16][C@@H:15]([OH:35])[CH2:14]1)=[O:11])[CH3:9].[Na+]>O>[CH3:6][CH2:7][C@@H:8]([C:10]([O:12][C@@H:13]1[C@@H:18]2[C@@H:19]([CH2:24][CH2:25][C@@H:26]([OH:34])[CH2:27][C@@H:28]([OH:33])[CH2:29][C:30]([OH:32])=[O:31])[C@@H:20]([CH3:23])[CH:21]=[CH:22][C:17]2=[CH:16][C@@H:15]([OH:35])[CH2:14]1)=[O:11])[CH3:9]
Reactant: CC[C@H](C)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)[O-])[C@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CC[C@H](C)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)O)[C@H]21
Temperature: 50 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
The pH was raised to 8.5 by addition of 2M sodium hydroxide in water (1.2 ml) and the solution was heated to 50° C. Acetonitrile (90 ml) was added to the mixture and then the mixture was stirred at elevated temperature for one hour. The mixture was allowed to cool to 20–25° C. (“ambient temperature”), was held at ambient temperature for two hours and then cooled to 5° C. and maintained at 5° C. for 12 hours, whereupon pravastatin sodium crystallized. The crystals were then isolated by filtration and washed with acetonitrile (2×10 ml) and dried under vacuum at 50° C. X-ray diffraction analysis revealed the presence of Form A. Pravastatin Form A was obtained in 92% yield.