Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@@H:12]([OH:14])[CH2:11][C@H:10]([C:15]([O:17][CH3:18])=[O:16])[C@H:9]1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.C1N=CN([C:37]([N:39]2[CH:43]=N[CH:41]=[CH:40]2)=[O:38])C=1.N1CCC[CH2:45]1>>[CH2:1]([N:8]1[CH2:13][C@@H:12]([O:14][C:37]([N:39]2[CH2:40][CH2:41][CH2:45][CH2:43]2)=[O:38])[CH2:11][C@H:10]([C:15]([O:17][CH3:18])=[O:16])[C@H:9]1[C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)[C@H]1C[C@H](O)CN(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@H](OC(=O)N2CCCC2)CN(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a solution of 2-benzyl 3-methyl(2S,3S,5S)-1-benzyl-5-hydroxypiperidine-2,3-dicarboxylate (144 mg, 0.000376 mol) in methylene chloride (2.0 mL, 0.031 mol) was added N,N-carbonyldiimidazole (73.1 mg, 0.000451 mol). The reaction was stirred at rt for 2 h. To the resulting mixture was added pyrrolidine (0.0470 mL, 0.000563 mol) and the reaction was stirred at rt overnight. The reaction was quenched with aq sodium bicarbonate, extracted with methylene chloride. The combined organic layers were dried, purified on silica gel (eluting with 0 to 40% EtOAc in hexane) to provide the carbamate compound (160 mg, 88.7%). MS (ESI): (M+H)+=481.2.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][N:12]=[C:13]([C:16]#[N:17])[C:14]#[N:15].NC1C=CC2C(=CC=CC=2)C=1.C(#N)CC#N.O.[NH2:35][NH2:36]>>[NH2:15][C:14]1[C:13](=[N:12][NH:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[C:16]([NH2:17])=[N:36][N:35]=1
Reactant: NN
Reactant: N#CC(C#N)=NNc1ccc2ccccc2c1
Agent: Nc1ccc2ccccc2c1
Solvent: O
Solvent: N#CCC#N
Product: NC1=NN=C(N)C1=NNc1ccc2ccccc2c1
Yield: 67 %

Procedure:
The title compound was prepared using 110 mg (0.5 mmol) of 2-[(naphthalen-2-yl)hydrazono]malononitrile, which was derived from 2-aminonaphthalene (143 mg, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. The hydrazine hydrate was added to the solution at a temperature of 75° C. despite the fact that the starting material had not fully dissolved. The solution cleared briefly and then a precipitate formed. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 86 mg (67%) of the title compound as a tan coloured solid.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:20]1[C:33]2[C:32](=[C:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[S:25][C:24]=2[CH:23]=[CH:22][CH:21]=1.O>C(Cl)Cl>[CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:37]2[CH2:38][CH2:39][C:34](=[C:32]3[C:33]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=4[S:25][C:26]4[C:31]3=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:35][CH2:36]2)=[O:8])=[CH:5][CH:4]=1
Reactant: c1ccc2c(c1)Sc1ccccc1C2=C1CCNCC1
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)c1ccc(C(=O)N2CCC(=C3c4ccccc4Sc4ccccc43)CC2)cc1
Yield: 40.5 %

Procedure:
To a magnetically stirred, ice-cooled solution of p-dimethylaminobenzoyl chloride (0.02 mole) and triethylamine (20 ml) in methylene chloride (300 ml) under an argon atmosphere was added dropwise a solution of 4-(9-thioxanthylidene)-piperidine (0.0133 mole) in methylene chloride (100 ml) over a twenty minute period. After stirring for 48 hours at room temperature, water (250 ml) was added and the mixture stirred for an additional 30 minutes. The layers were separated and the organic layer was washed with water (100 ml), 5% sodium hydroxide (2×200 ml) and water (250 ml), and then dried over sodium sulfate, filtered and stripped under reduced pressure to a dark orange oil. The product was purified by low pressure column chromatography using a 25×1000 mm column packed with 250 g. of silica gel absorbent and eluted with ethyl acetate to yield 2.3 grams of the product. Recrystallization from toluene yielded 2.1 g. of product, m.p. 178°-186° C. (decomp.)
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH:14]=O>>[CH2:1]([NH:3][CH2:14][C:5]1[CH:6]=[CH:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]=1)[CH3:2]
Reactant: CCN
Reactant: O=Cc1ccc2ccccc2n1
Product: CCNCc1ccc2ccccc2n1

Procedure:
prepared by reaction of ethylamine with quinoline-2-carbaldehyde
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[ClH:12].CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:37][C:38]([CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)([CH2:42][CH2:43][CH2:44][CH2:45][B:46]([OH:48])[OH:47])[C:39]([OH:41])=[O:40].C(N(CC)CC)C>CN(C=O)C.Cl>[ClH:12].[NH2:37][C:38]([CH:49]1[CH2:50][CH2:51][N:52]([C:9](=[O:11])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:53][CH2:54]1)([CH2:42][CH2:43][CH2:44][CH2:45][B:46]([OH:48])[OH:47])[C:39]([OH:41])=[O:40]
Reactant: NC(CCCCB(O)O)(C(=O)O)C1CCNCC1
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(CCCCB(O)O)(C(=O)O)C1CCN(C(=O)Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 35 %

Procedure:
A solution of 4-fluorobenzeneacetic acid (126 mg, 0.816 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (156 mg, 0.816 mmol) and 1-hydroxybenzotriazole hydrate (125 mg, 0.816 mmol) in dry DMF (4 mL) was stirred for 30 minutes under an atmosphere of nitrogen. To the stirring solution was added a solution of crude 2-amino-6-borono-2-(piperidin-4-yl)hexanoic acid dihydrochloride (Example 26-A, Step 1, 150 mg, 0.371 mmol) in dry DMF (4 mL) in one portion. Triethylamine (0.31 mL, 2.23 mmol) was added and the resulting opaque mixture was stirred at room temperature for 1.75 hours. At the end of the reaction the solution was diluted with 1 N HCl and washed with ethyl acetate (2×), prior to concentration of the combined organic layers. The crude product was purified by reverse phase HPLC [Phenomenex Luna 250×30.00 mm, 10 micron column. 40 mL/min flow rate. Gradient: solvent A is 0.07% TFA in acetonitrile; solvent B is 0.10% TFA in water. Run 1—5% to 50% A over 24 min, then 50% to 100% A over 1 min. Run 2—5% to 40% A over 24 min, then 40% to 100% A over 1 min. Run 3—5% to 30% A over 24 min, then 30% to 100% A over 1 min]. Product fractions were pooled and concentrated, and the residue was taken up in 0.5N HCl (4 mL)/acetonitrile (6 mL) and concentrated. The residue was once again treated with 0.5N HCl (4 mL)/acetonitrile (6 mL) and concentrated and dried under high vacuum overnight to give 2-amino-6-borono-2-{1-[(4-fluorophenyl)acetyl]piperidin-4-yl}hexanoic acid hydrochloride (56 mg, 35%) as a white solid. 1H NMR (MeOH-d6, 400 MHz) δ 7.28 (m, 2H), 7.07 (m, 2H), 4.69 (m, 1H), 4.15 (m, 1H), 3.78 (m, 2H), 3.08 (m, 1H), 2.63 (m, 1H), 2.14 (m, 1H), 1.89 (m, 3H), 1.64 (m, 1H), 1.45 (m, 4H), 1.30-0.95 (m, 2H), 0.84 (bt, J=6.8 Hz, 2H). ESI+ MS found for C19H28BFN2O5 m/z 377.3 (M−18+H), 359.4 (M−2×18+H); ESI− MS m/z 393.4 (M−H), 375.4 (M−18−H).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5]C=[CH:3][CH:2]=1.[CH3:8][C:9](O)([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10].[CH3:18]CCCCC>>[CH:14]([CH:13]1[C:5]2[C:8](=[CH:3][CH:2]=[C:1]([CH3:7])[CH:6]=2)[C:9]([CH3:10])([CH3:18])[CH2:11][CH2:12]1)([CH3:16])[CH3:15]
Reactant: Cc1ccccc1
Reactant: CCCCCC
Reactant: CC(C)=CCCC(C)(C)O
Product: Cc1ccc2c(c1)C(C(C)C)CCC2(C)C
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
1050 g of sulphuric acid are provided and a mixture of 1.5 l of toluene and 497 g of 2,6-dimethyl-hept-5-en-2-ol are added dropwise during 35 minutes while cooling (10° C.). The mixture is stirred at room temperature for 1.5 hours. The mixture is now diluted with hexane, poured on to ice, washed neutral, dried and evaporated. After distillation there are obtained 455 g of 1-isopropyl-4,4,7-trimethyl-1,2,3,4-tetrahydro-naphthalene (purity 75%).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C:13]([S:16][C:17](=O)[CH3:18])([CH3:15])[CH3:14])=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].BrC[CH:22]1[CH2:26][CH2:25]C[O:23]1.[O-]CC.[Na+]>C(O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:12])[C:13]([CH3:15])([S:16][CH2:17][CH:18]2[CH2:25][CH2:26][CH2:22][O:23]2)[CH3:14])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCC1CCCO1
Reactant: CC(=O)SC(C)(C)C(=O)Nc1cc(C(C)(C)C)on1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(SCC1CCCO1)C(=O)Nc1cc(C(C)(C)C)on1
Temperature: 50 °C
Yield: 71.8 %

Procedure:
To a solution of 100 mg (0.35 mmol) of thioacetic acid S-[1-(5-tert-butyl-isoxazol-3-ylcarbamoyl)-1-methyl-ethyl]ester in ethanol (2 mL) were added 70 mg (0.42 mmol) of 2-(bromomethyl)tetrahydrofuran and 340 μL (1.05 mmol) of sodium ethoxide solution (21% in ethanol) at room temperature. The reaction was heated to 50° C. for 18 h. The reaction mixture was concentrated under reduced pressure and the crude purified by column chromatography (silica, eluent: heptanes, 0-20% ethyl acetate) to afford 82 mg of N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-2-(tetrahydro-furan-2-ylmethylsulfanyl)-propionamide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]([CH:13]=1)[C:9]([NH:11][NH2:12])=[O:10])([O-:3])=[O:2].[F:21][C:22]([F:32])([F:31])[C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O>>[F:21][C:22]([F:31])([F:32])[C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=[N:12][NH:11][C:9](=[O:10])[C:8]1[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[O:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: NNC(=O)c1cc([N+](=O)[O-])ccc1Oc1ccccc1
Product: O=C(NN=Cc1cccc(C(F)(F)F)c1)c1cc([N+](=O)[O-])ccc1Oc1ccccc1

Procedure:
A mixture of 5-nitro-2-phenoxy-benzoic acid methyl ester (4.0 g, 14.7 mmol) and hydrazine (5 mL, 80%) was refluxed for 4 h to yield 5-nitro-2-phenoxy-benzoic acid hydrazide (2.97 g, 74%). The title compound was prepared from 5-nitro-2-phenoxy-benzoic acid hydrazide and 3-trifluoromethyl-benzaldehyde by a procedure similar to Example 22. 1H NMR (DMSO-d6): 12.20 (s, 1H), 8.52 (s, 1H), 8.43 (s, 1H), 8.35 (d, J=7.2 Hz, 1H), 8.17 (s, 1H), 8.10 (d, J=6.6 Hz, 1H), 7.81 (m, 1H), 7.75 (t, J=6.6 Hz, 1H), 7.54 (t, J=7.2 Hz, 1H), 7.35 (m, 2H), 7.27 (d, J=7.2 Hz, 1H), 7.03 (m, 2H).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C)C=O>[N:13]([CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[N+:14]=[N-:15]
Reactant: ClCCOCc1ccccn1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCOCc1ccccn1
Reaction time: 8 h

Procedure:
A stirred suspension of 2-(2-chloroethoxymethyl)pyridine hydrochloride and sodium azide (9.8 g.) in dry dimethylformamide (103 ml.) is maintained at 95° for 5 hours and then set aside overnight at room temperature. Following dilution with water and filtration, the filtrate is concentrated and the residue purified by chromatography on a dry column of alumina using ethanol. The product is basified with potassium carbonate (6.5 g.) in water (3 ml.) and the anhydrous residue is extracted with isopropyl alcohol (3 × 50 ml.). Concentration of the extracts gives 2-(2-azidoethoxymethyl)pyridine. Hydrogenation of the azido compound in isopropyl alcohol over platinum oxide catalyst gives 2-(2-aminoethoxymethyl)pyridine.
Reaction SMILES: C=O.[CH3:3][C:4]1[S:8][C:7]([NH:9][C:10]([C:12]2[CH:21]=[C:20]3[C:15]([C:16](=[O:28])[N:17]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:18]4=[N:19]3)=[CH:14][CH:13]=2)=[O:11])=[N:6][CH:5]=1.[CH3:29]C([O-])=O.[Na+]>CC(O)=O.O>[CH2:29]=[C:22]1[C:18]2=[N:19][C:20]3[C:15]([C:16](=[O:28])[N:17]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[CH:14][CH:13]=[C:12]([C:10]([NH:9][C:7]1[S:8][C:4]([CH3:3])=[CH:5][N:6]=1)=[O:11])[CH:21]=3
Reactant: CC(=O)[O-]
Reactant: Cc1cnc(NC(=O)c2ccc3c(=O)n4c(nc3c2)CCCCCC4)s1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C=C1CCCCCn2c1nc1cc(C(=O)Nc3ncc(C)s3)ccc1c2=O
Yield: 144 %

Procedure:
Paraformaldehyde (10 mg), N-(5-methylthiazol-2-yl)-13-oxo-7,8,9,10,11,13-hexahydro-6H-azocino[2,1-b]quinazoline-3-carboxamide (60 mg, 0.16 mmol) and NaOAc (3 mg, 0.0365 mmol) in 5 mL HOAc was stirred at 120° C. overnight in a sealed tube. The completion was monitored by TLC and LC-MS. The sealed tube was then placed in water until cool. The suspension was diluted with water (30 mL) and adjusted pH to 8, then extracted with ethyl acetate (3×50 mL). The organic phase was concentrated to give crude product and 20 mg of the desired product was obtained by column chromatography. MS (ESI): 381 (MH+); 1H NMR (300 MHz, CDCl3) δ 8.45-8.42 (d, J=8.22 Hz, 1H), 8.27 (s, 1H), 8.04-8.00 (dd, J=8.39, 1.61 Hz, 1H), 7.28 (s, 2H), 5.52 (s, 1H), 5.30 (s, 1H), 4.39-4.33 (m, 2H). 2.72-2.59 (m, 2H), 2.42 (s, 3H), 1.96-1.88 (m, 2H), 1.72-1.68 (m, 2H), 1.56-1.51 (m, 2H).
Reaction SMILES: Cl.[CH2:2]([N:6]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C@H:7]([C:13]([OH:15])=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH:3]([CH3:5])[CH3:4].[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH:38][C@H:39]([C:44](O)=[O:45])[CH2:40][C:41](=[O:43])[NH2:42])(=[O:37])=[O:36])=[CH:31][CH:30]=1>>[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH:38][C@H:39]([C:44]([NH:12][CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]([N:6]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:2][CH:3]([CH3:5])[CH3:4])[C:13]([OH:15])=[O:14])=[O:45])[CH2:40][C:41]([NH2:42])=[O:43])(=[O:36])=[O:37])=[CH:31][CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](CC(N)=O)C(=O)O)cc1
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: Cc1ccc(S(=O)(=O)N[C@@H](CC(N)=O)C(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc(N)cc2)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine hydrochloride (400 mg, 1.03 mmol, example 5, step C) as described in general procedure Bc using Nα-(4-methylbenzenesulfonyl)-L-asparagine (286 mg, 1.0 mmol) which was prepared in step A this example. The final product, Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-Nε-[N′α-(4-methylbenzenesulfonyl)-L-asparagyl]-L-lysine was subsequently hydrogenolysed following the indications of general procedure E. Purification by HPLC gave the desired material (185 mg, 76%).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].[OH-].[Na+:33].CC(O)C>O>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:33]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.6 %

Procedure:
Fluvastatin methyl ester (2.0 g) was added to a solution of NaOH (1 eq.) in water. The mixture was stirred at about 70EC for 2 h until the raw material wasn't observed by HPLC. After this time, propan-2-ol (10 ml) was dripped and the solution was cooled slowly to room temperature. Another 40 ml of propan-2-ol (in 3 portions) were added at room temperature to the solution but no precipitation was ECcurred. The solution was stirred overnight and a gel-like precipitate formed. The mixture was heated to reflux to dissolve the gel. The mixture was then allowed to cool to room temperature. A yellow slurry was obtained. After stirring overnight, another 15 ml of propan-2-ol were added dropwise. The product was isolated by filtration under nitrogen, washed with propan-2-ol (25 ml) and dried at 50EC in a vacuum oven for 24 h to obtain 0.46 g (22.6%) of fluvastatin sodium Form XLIII.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C(N(CC)C(C)C)(C)C.C([O:23][C:24](=O)[CH:25]=[C:26]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1)[CH2:27]Br)C>C(#N)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([N:6]1[CH2:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:38])([F:39])[F:37])[CH:31]=2)=[CH:25][C:24]1=[O:23])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: CCOC(=O)C=C(CBr)Oc1cccc(C(F)(F)F)c1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)[C@H](CC(C)C)N1CC(Oc2cccc(C(F)(F)F)c2)=CC1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
A mixture of (L)-leucine methyl ester hydrochloride (0.79 g, 4.34 mmol) in acetonitrile (9.5 mL) was treated with N,N-diisopropylethylamine (0.70 mL, 4.26 mmol). After addition was complete, the mixture was stirred at 60° C. for 1 h. At this time, the reaction was cooled to 25° C., treated with N,N-diisopropylethylamine (0.70 mL, 4.26 mmol) and acetonitrile (9.5 mL) and then heated to 80° C. Upon reaching 80° C., the reaction was treated with a solution of 4-bromo-3-(3-trifluoromethyl-phenoxy)-but-2-enoic acid ethyl ester (1.40 g, 3.96 mmol) in acetonitrile (9.5 mL). After the addition was complete the reaction mixture was heated to 100° C. and stirred overnight. At this time, the reaction mixture was cooled to 25° C. and concentrated in vacuo. The residue was diluted with dichloromethane (100 mL) and was washed with a 2N aqueous hydrochloric acid solution (1×100 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL), a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, rinsed with dichloromethane and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 15-50% ethyl acetate/hexanes) afforded (S)-4-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-pentanoic acid methyl ester (0.86 g, 59%) as a light, brown solid: HR-ES-MS m/z calculated for C18H20NO4F3 [M+H]+ 372.1417, observed 372.1418; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.88 (d, J=6.6 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H), 1.29-1.55 (m, 1H), 1.56-1.68 (m, 1H), 1.73-1.90 (m, 1H), 3.66 (s, 3H), 4.19 (d, J=18.1 Hz, 1H), 4.26 (d, J=18.1 Hz, 1H), 4.75 (dd, J=11.4, 4.6 Hz, 1H), 4.95 (s, 1H), 7.64-7.78 (m, 4H).
Reaction SMILES: I[C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH3:15])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]([N:33]([CH3:35])[CH3:34])[C:28]([C:31]#[CH:32])=[N:29][CH:30]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]([N:33]([CH3:35])[CH3:34])[C:28]([C:31]#[C:32][C:2]3[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][N:9]4[CH2:14][CH2:13][CH:12]([CH3:15])[CH2:11][CH2:10]4)=[CH:4][CH:3]=3)=[N:29][CH:30]=2)=[CH:21][CH:20]=1
Reactant: CC1CCN(CCOc2ccc(I)cc2)CC1
Reactant: C#Cc1ncc(-c2ccc(Cl)cc2)cc1N(C)C
Product: CC1CCN(CCOc2ccc(C#Cc3ncc(-c4ccc(Cl)cc4)cc3N(C)C)cc2)CC1

Procedure:
The product was prepared analogously to Example 7.1 e starting from 1-[2-(4-iodophenoxy)ethyl]-4-methylpiperidine and [5-(4-chlorophenyl)-2-ethynylpyridin-3-yl]dimethylamine. Yield: 34 mg (5% of theoretical); C29H32ClN3O (M=474.037); calc.: molpeak (M+H)+:474/476 (Cl); found: molpeak (M+H)+:474/476 (Cl); HPLC-MS: 5.40 minutes (method D).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[CH:15]([NH:17][NH2:18])=O>C(O)CCC>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]3[N:3]([CH:15]=[N:17][N:18]=3)[N:4]=2)=[CH:9][CH:10]=1
Reactant: NNC=O
Reactant: Clc1ccc(-c2ccc(Cl)nn2)cc1
Solvent: CCCCO
Product: Clc1ccc(-c2ccc3nncn3n2)cc1

Procedure:
A mixture of 9.0 g. of 3-chloro-6-(p-chlorophenyl)pyridazine (prepared as in Example 16), 5.1 g. of formylhydrazine and 60 ml. of butyl alcohol is heated at reflux temperature for 40 hours. The reaction mixture is cooled, filtered and the solid washed with petroleum ether and with water. The material is then heated with 125 ml. of ethanol and the insoluble material is collected by filtration. The filtrate is cooled and the precipitate is collected and combined with the insoluble material collected above. The combined solids are recrystallized from 130 ml. of ethyl alcohol to provide the product of the example as crystals, m.p. 216°-218° C.
Reaction SMILES: [CH3:1][N:2]([C:13]1[N:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=1)[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]#[C:10][CH2:11]O)[CH2:5][CH2:4]1.CS([Cl:24])(=O)=O.N1C(C)=CC=CC=1C.O>C(Cl)Cl>[Cl:24][CH2:11][C:10]#[C:9][C@H:6]1[CH2:7][CH2:8][C@H:3]([N:2]([CH3:1])[C:13]2[N:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=2)[CH2:4][CH2:5]1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(N(C)[C@H]2CC[C@H](C#CCO)CC2)nn1
Solvent: ClCCl
Solvent: O
Solvent: Cc1cccc(C)n1
Product: Cc1ccc(N(C)[C@H]2CC[C@H](C#CCCl)CC2)nn1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A solution of 0.246 g (0.95 mmol) of trans-3-{4-[Methyl-(6-methyl-pyridazin-3-yl)-amino]-cyclohexyl}-prop-2-yn-1-ol in 7 ml CH2Cl2 was treated at 0° C. with 0.081 ml (1.04 mmol) methanesulfonylchloride and 0.17 ml (1.42 mmol) 2,6-lutidine. The reaction was stirred for 22 h at room temperature, water (1 ml) was added and stirred for 5 min. After extraction with aqueous saturated NaHCO3/Et2O(3×), the organic phase was washed with aqueous 10% NaCl, dried over Na2SO4 and evaporated to yield 0.285 g of crude trans-[4-(3-Chloro-prop-1-ynyl)-cyclohexyl]-methyl-(6-methyl-pyridazin-3-yl)-amine, MS: 278 (MH+, 1Cl).
Reaction SMILES: [C:1]([NH:3][C:4]([N:6](C#N)[CH2:7][CH2:8][S:9][CH2:10][C:11]1[N:12]=[CH:13][NH:14][C:15]=1[CH3:16])=[NH:5])#[N:2].[CH3:19]N>C(O)C>[C:1]([N:3]=[C:4]([NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[N:12]=[CH:13][NH:14][C:15]=1[CH3:16])[NH:5][CH3:19])#[N:2]
Reactant: CN
Reactant: Cc1[nH]cnc1CSCCN(C#N)C(=N)NC#N
Solvent: CCO
Product: CNC(=NC#N)NCCSCc1nc[nH]c1C
Reaction time: 47 h

Procedure:
N,N'-Dicyano-N'-[2-(5-methylimidazol-4-ylmethylthio)ethyl]guanidine (527 mg) was added to a solution of CH3NH2 in ethanol (40%, 3.1 g) and stirred for 47 hrs. at room temperature. After concentration under a reduced pressure, the residue was triturated with CH3CN. The insuluble starting material was filtered off and the filtrate was concentrated under a reduced pressure and chromatographed on SiO2 [eluant: CH3CN-CH3OH (4:1)]. The resulting crude product was purified by preparative thin layer chromatography [SiO2, CH3 --COOC2H5 --CH3OH-- 28% NH3 (aq) (10:1:1)] and recrystallized from CH3CN to give N"-cyano-N-methyl-N'-[2-(5-methylimidazol-4-ylmethylthio)ethyl]guanidine (1.0 mg). m.p. 135°-137° C.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.[CH3:13][N:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][C:20]([O:22][CH3:23])=[O:21].O>C(O)(=O)C.C(Cl)(Cl)Cl>[OH:12][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([OH:11])=[CH:3][C:2]=1[C:18]1[N:14]([CH3:13])[C:15]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:17]=1
Reactant: COC(=O)Cc1cccn1C
Reactant: O=C1C=CC(=O)c2ccccc21
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc(-c2cc(O)c3ccccc3c2O)n1C
Yield: 12 %

Procedure:
40 millimol of 1,4-naphthoquinone and 10 millimol of methyl 2-(N-methyl-1H-pyrrolyl)acetate were stirred in 50 ml of glacial acetic acid in a round-bottomed flask for 2 hours at room temperature. The reaction mixture was diluted with 300 ml of chloroform and the resulting mixture was then poured into a large volume of water (300 ml). The organic phase was then separated out and washed four times with 100 ml of water and finally with saturated aqueous NaCl solution. The resulting organic phase was dried over Na2SO4 and then concentrated under vacuum. The methyl [5-(1,4-dihydroxynaphthalen-2-yl)-1-methyl-1H-pyrrol-2-yl]acetate was thus isolated in a yield of 12% after purification by chromatography on a column of silica.