Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:13]1([CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CCOCC.O.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>[C:13]1([CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:2]2[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=[N:4][CH:3]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: OB(O)c1ccccc1-c1ccccc1OCc1ccccc1
Reactant: CCOC(=O)c1cncc(Br)c1
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: O
Solvent: CCOCC
Product: CCOC(=O)c1cncc(-c2ccccc2-c2ccccc2OCc2ccccc2)c1
Temperature: 90 °C
Yield: 80.6 %

Procedure:
A mixture of ethyl 5-bromonicotinate (46 mg, 0.2 mmol), {2′-[(phenylmethyl)oxy]-2-biphenylyl}boronic acid (61 mg, 0.2 mmol), potassium carbonate (221 mg, 1.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol) was stirred and heated at 90° C. under nitrogen for 2 hours. After cooling the mixture was diluted with ether/water and the organic phase dried (magnesium sulphate), evaporated and chromatographed on silica eluting with ethyl acetate/iso-hexane (1:5) to give 66 mg of colourless gum.
Reaction SMILES: [CH3:1][C:2]1[S:17][C:5]2[O:6][C:7]3[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=O)[C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[CH3:1][C:2]1[S:17][C:5]2[O:6][C:7]3[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:8]=3[N:9]=[C:10]([N:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(s1)Oc1c(C)cccc1NC2=O
Reactant: CN1CCNCC1
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc2c(s1)Oc1c(C)cccc1N=C2N1CCN(C)CC1

Procedure:
In the same manner as in Example 125 and using 2,9-dimethylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one, phosphorus oxychloride, N,N-dimethylaniline and 1-methylpiperazine, 2,9-dimethyl-4-(4-methylpiperazin-1-yl)thieno[2,3-b][1,5]benzoxazepine is obtained.
Reaction SMILES: FC(F)(F)COP([CH2:13][C:14]([O:16][CH3:17])=[O:15])(=O)OCC(F)(F)F.C1OCCOCCOCCOCCOCCOC1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[N:55]1([CH2:60][C:61]([C:63]2[CH:64]=[C:65]([CH:68]=[CH:69][CH:70]=2)[C:66]#[N:67])=O)[CH:59]=[CH:58][CH:57]=[N:56]1>O1CCCC1>[C:66]([C:65]1[CH:64]=[C:63](/[C:61](/[CH2:60][N:55]2[CH:59]=[CH:58][CH:57]=[N:56]2)=[CH:13]\[C:14]([O:16][CH3:17])=[O:15])[CH:70]=[CH:69][CH:68]=1)#[N:67]
Reactant: N#Cc1cccc(C(=O)Cn2cccn2)c1
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)/C=C(/Cn1cccn1)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 32.4 %

Procedure:
To a solution of bis(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate (0.39 ml, 1.87 mmol) in 5 ml anhydrous tetrahydrofuran was added a solution of 18-crown-6 (2 g, 7.8 mmol) in 5 ml anhydrous tetrahydrofuran. Reaction was cooled to −78° C. to which a 0.5M solution of potassium bis(trimethylsilyl)amide in toluene (0.93 ml, 1.87 mmol) was added all at once. The reaction mixture was stirred at −78° C. for 20 minutes after which a solution of 3-[2-(1H-1-pyrazolyl)acetyl]-benzonitrile (330 mg, 1.56 mmol) in 5 ml anhydrous tetrahydrofuran was added dropwise over several minutes. Reaction was gradually allowed to warm to room temperature and stirred for 5 hours. Reaction was then quenched with a saturated ammonium chloride solution (10 ml) and extracted with 2×25 ml diethyl ether. Combined organic layers were washed with 2×25 ml water, 2×25 ml saturated brine solution, dried over magnesium sulfate, filtered and concentrated to a brown residue. Crude residue was chromatographed on silica gel using a gradient of 5% EtOAc in hexane containing 0.1% triethylamine to 20% EtOAc in hexane containing 0.1% triethylamine to give methyl (E)-3-(3-cyanophenyl)-4-(1H-1-pyrazolyl)-2-butenoate (135 mg, 32%) as a clear oil after drying. H1NMR (CDCl3) 3.521 (s, #H); 4.98 (s, 2H); 5.694 (s, H); 6.237-6.247 (t, H); 7.296-7.593 (m, 6H). NOE experiment confirmed the stereochemical configuration.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[CH:30]=[C:31]([C:39]([F:42])([F:41])[F:40])[C:32]3[N:36]=[C:35]([CH3:37])[NH:34][C:33]=3[CH:38]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([O:28][C:29]5[CH:30]=[C:31]([C:39]([F:40])([F:41])[F:42])[C:32]6[N:36]=[C:35]([CH3:37])[NH:34][C:33]=6[CH:38]=5)[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1nc2c(C(F)(F)F)cc(Oc3cc(Cl)ncn3)cc2[nH]1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C(F)(F)F)c5nc(C)[nH]c5c4)ncn3)CC1)C(=O)N2

Procedure:
140 mg (0.510 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 167 mg (0.500 mmol) 6-(6-chloro-pyrimidin-4-yloxy)-2-methyl-4-trifluoromethyl-1H-benzimidazole and 0.261 mL (1.50 mmol) DIPEA in 1.5 mL DMF were stirred for 10 h at RT. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were combined and freeze-dried.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:18]=3[CH3:24])[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2].[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[C:21]([NH:23][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][C:26]([F:25])=[CH:27][CH:28]=4)[CH:20]=[CH:19][C:18]=3[CH3:24])[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)c1cncc2c(COc3cc(N)ccc3C)csc12
Product: CCOC(=O)c1cncc2c(COc3cc(NC(=O)c4ccc(F)cc4)ccc3C)csc12

Procedure:
3-[5-(4-Fluoro-benzoylamino)-2-methyl-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester was prepared from 3-(5-amino-2-methyl-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (from Example 23 supra) and 4-fluorobenzoyl chloride (Aldrich) following the procedure described in Example 10 as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH2:22][OH:23])[CH:16]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].Cl>N1C=CC=CC=1>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][CH2:22][O:23][S:26]([CH3:25])(=[O:28])=[O:27])[CH:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1c(C(=O)c2cccc(CCO)c2)cnn1-c1ccc(F)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCc1cccc(C(=O)c2cnn(-c3ccc(F)cc3)c2N)c1
Reaction time: 2 h
Yield: 86.3 %

Procedure:
To a solution of 5-amino-1-(4-fluorophenyl)-4-[3-(2-hydroxyethyl)benzoyl]pyrazole (0.8 g, 2.5 mmol) in pyridine (10 ml) was added methanesulfonyl chloride (0.29 ml, 3.7 mmol). After 2 h, the reaction mixture was poured into 2 N hydrochloric acid (40 ml) and the product was extracted into ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (elution gradient: 40-100% ethyl acetate/hexane) to give 5-amino-1-(4-fluorophenyl)-4-[3-(2-methanesulfonyloxyethyl)benzoyl]pyrazole (0.87 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[C:22]([CH3:28])([CH3:27])[C:23](C#N)=[O:24]>C1COCC1>[CH3:27][C:22]1([CH3:28])[C:23](=[O:24])[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)[O:10]1
Reactant: CSc1ccc(C(=O)Cc2cccc(F)c2)cc1
Reactant: CC(C)(Br)C(=O)C#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1ccc(C2=C(c3cccc(F)c3)C(=O)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
To a stirred solution of 2-(3-fluorophenyl)-1-{4-(methylthio)phenyl}-ethan-1-one (100 g) in 1 L dry THF, was added portion-wise 26 g of 95 % sodium hydride at 0° C. The reaction solution was stirred at the same temperature for 1 hour. Then 69 g of α-bromo-isobutyryl cyanide diluted in 25 ml dry THF was added dropwise to the stirred solution at 0° C. The reaction mixture was stirred overnight while allowing to warm gradually to room temperature. The solution was concentrated in vacuo, to which was added 50 ml water. The aqueous solution was extracted with ethylacetate (1 L). The organic layer was concentrated in vacuo and purified by column chromatography (hexane/ethylacetate=6:1) to give 102 g of 2,2-dimethyl-4-(3-fluorophenyl)-5-{4-(methylthio)phenyl}-3(2H)-furanone. mp: 106° C. NMR: δ1.55 (s, 6H), 2.50 (s. 3H), 6.97-7.11 (m, 3H), 7.18 (d, J=9.0 Hz, 2H), 7.26-7.36 (m, 1H), 7.55 (d, J=9.0 Hz, 2H).
Reaction SMILES: C[N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[N:3]1.N([CH2:33][C:34]([CH3:37])([OH:36])[CH3:35])N>>[CH3:33][C:34]([OH:36])([CH3:37])[CH2:35][N:3]1[C:4]([C:13]2[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:29][CH:30]=2)=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[CH:6]=[N:2]1
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Reactant: CC(C)(O)CNN
Product: CC(C)(O)Cn1ncc(-c2ccncc2)c1-c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
Following the procedure for the preparation of 2-[4-(1-Methyl-4-pyridin4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting 1-Hydrazino-2-methyl-propan-2-ol provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.37 (d, J=5.8 Hz, 2 H), 8.24 (d, J=8.3 Hz, 1 H), 8.09 (d, J=9.1 Hz, 1 H), 7.87 (s, 1H), 7.85 (d, J=7.9 Hz, 1H), 7.76 (m, 1 H), 7.72 (m, 1H), 7.17 (m, 4 H), 7.00 (d, J=6.2 Hz, 2H), 5.42 (s, 2H) 3.89 (s, 2H), 1.04 (s, 6H); MS: (M+H m/z=451.2).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18]>>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH:18][C:6]1[CH:5]=[CH:4][C:3]2[C:2]([NH:18][CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[O:14][CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: COc1ccccc1CN
Reactant: Clc1ccc2c(Br)cccc2n1
Product: COc1ccccc1CNc1ccc2c(NCc3ccccc3OC)cccc2n1

Procedure:
The title compound, MS: m/e=400.3 (M+H+), was prepared in accordance with the general method of example 1 from 5-bromo-2-chloroquinoline and 2-methoxybenzylamine in step A and step B.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[O:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25](O)=[O:26])[CH:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[NH2:31][CH:32]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[O:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([NH:31][CH:32]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33]3)=[O:26])[CH:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(-c2cc3nccc(-c4cccc(C(=O)O)c4)c3o2)cc(OC)c1OC
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Product: COc1cc(-c2cc3nccc(-c4cccc(C(=O)NC5CCN(C(=O)OC(C)(C)C)C5)c4)c3o2)cc(OC)c1OC
Yield: 64 %

Procedure:
Starting from 3-[2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridin-7-yl]benzoic acid (0.099 mmol) and (+/−)-3-amino-1-N—BOC-pyrrolidine (0.102 mmol) the product is prepared analogously to “A43” and obtained as yellow solid in a yield of 64%. HPLC (method A): Rt 2.68 min (purity 99.3%); LCMS (ESI+) (method E): Rt 2.11 min, M+H+ 574.3 m/z; 1H NMR (500 MHz, DMSO-d6) δ[ppm] 8.82 (s, 1H), 8.71 (d, J=6.3, 1H), 8.62 (d, J=5.2, 1H), 8.28 (d, J=8.0, 1H), 8.06 (d, J=7.9, 1H), 7.79 (s, 1H), 7.74 (dd, J=13.0, 6.4, 2H), 7.37 (s, 2H), 4.46 (s, 1H), 3.93 (s, 6H), 3.75 (s, 3H), 3.48-3.39 (m, 1H), 3.34 (d, J=7.0, 2H), 3.22 (d, J=4.2, 1H), 2.19-2.09 (m, 1H), 1.99-1.86 (m, 1H), 1.41 (s, 9H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][C:8]1[C:13]([C:14]([OH:16])=[O:15])=[C:12]([NH:17][C:18](=[O:24])[C@H:19]([CH:21]([CH3:23])[CH3:22])[NH2:20])[CH:11]=[CH:10][CH:9]=1.[CH:25]1[C:37]2[CH:36]([CH2:38][O:39][C:40](Cl)=[O:41])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]=2[CH:28]=[CH:27][CH:26]=1.Cl>O1CCOCC1.O>[CH:25]1[C:37]2[CH:36]([CH2:38][O:39][C:40]([NH:20][C@H:19]([C:18]([NH:17][C:12]3[CH:11]=[CH:10][CH:9]=[C:8]([CH3:7])[C:13]=3[C:14]([OH:16])=[O:15])=[O:24])[CH:21]([CH3:22])[CH3:23])=[O:41])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]=2[CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: Cc1cccc(NC(=O)[C@@H](N)C(C)C)c1C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(NC(=O)[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(C)C)c1C(=O)O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 73 %

Procedure:
284 mg of sodium carbonate and 336 mg of 6-methyl-2-(L-valylamino)benzoic acid were dissolved in a mixture consisting of 17 ml of 1,4-dioxane and 12 ml of water, followed by adding dropwise a solution of 345 mg of 9-fluorenylmethoxycarbonyl chloride in 7 ml of 1,4-dioxane under ice-cooling. After stirring for 3.5 hours at room temperature, the reaction mixture was poured into water, acidified with concentrated hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with a saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by a silica gel column chromatography (eluting solution: hexane-ethyl acetate-acetic acid) to give 460 mg of 2-{[N-(9-fluorenylmethoxy-carbonyl)-L-valyl]amino}-6-methylbenzoic acid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)=[C:9]([CH3:25])[N:8]([C@@H:26]3[CH2:29][C@H:28]([CH2:30]O)[CH2:27]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[NH:43]1[CH2:49][CH2:48][CH2:47][C@@H:44]1[CH2:45][OH:46]>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:12]=3)=[C:9]([CH3:25])[N:8]([C@@H:26]3[CH2:27][C@H:28]([CH2:30][N:43]4[CH2:49][CH2:48][CH2:47][C@@H:44]4[CH2:45][OH:46])[CH2:29]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: OC[C@H]1CCCN1
Reactant: Cc1c(-c2cccc(OCc3ccccc3)c2)c2c(N)ncnc2n1[C@H]1C[C@@H](CO)C1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1c(-c2cccc(OCc3ccccc3)c2)c2c(N)ncnc2n1[C@H]1C[C@@H](CN2CCC[C@@H]2CO)C1

Procedure:
The title compound is prepared in analogy to Example 116 starting from 0.35 g (0.84 mmol) cis-{3-[4-amino-5-(3-benzyloxy-phenyl)-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl}-methanol and 0.328 g (1.69 mmol) p-toluenesulfonyl chloride in 3.5 ml dry pyridine, followed by 0.631 ml (6.33 mmol) D-prolinol (Fluka, Buchs, Switzerland). Analytical HPLC: tR=9.08 min (Grad 1); ES-MS: m/eo=498.2; NMR (DMSO-d6; not all signals reported): 8.07/s (1H), 7.25-7.5/several m's (6H), 7.02/“d” (1H); 6.94/s (1H); 6.89/“d” (1H); 5.4-6.0/b (NH2); 5.13/s (2H); 4.78/m (1H); 4.34/b (OH); 2.22/s (3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[CH2:12][C:13](N(OC)C)=[O:14].[CH3:19][Mg]Br.[Cl-].[NH4+]>CCOCC>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[CH2:12][C:13](=[O:14])[CH3:19]
Reactant: C[Mg]Br
Reactant: COCOc1ccc(CC(=O)N(C)OC)c(Br)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: COCOc1ccc(CC(C)=O)c(Br)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 2-(2-bromo-4-(methoxymethoxy)phenyl)-N-methoxy-N-methylacetamide (4.30 g) in ether (93 ml) was added methyl magnesium bromide (3 M in ether, 63 mL) dropwise at 0° C. After addition, the solution was stirred at 0° C. for 1.5 hr. The mixture was poured into saturated aqueous ammonium chloride, and extracted with ethyl acetate (100 mL×2). The organic phase was dried over anhydrous sodium sulfate, The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to afford the title compound (23 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[NH:7][C:6]([C:13]([OH:15])=O)=[CH:5]2.[CH3:16][CH:17]([NH:19][C:20]1[C:21]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:22][CH:23]=[CH:24][CH:25]=1)[CH3:18].C(N=C=NCCCN(C)C)C>>[CH3:18][CH:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[N:26]1[CH2:27][CH2:28][N:29]([C:13]([C:6]2[NH:7][C:8]3[C:4](=[CH:3][C:2]([Br:1])=[C:10]([O:11][CH3:12])[CH:9]=3)[CH:5]=2)=[O:15])[CH2:30][CH2:31]1)[CH3:16]
Reactant: CC(C)Nc1cccnc1N1CCNCC1
Reactant: COc1cc2[nH]c(C(=O)O)cc2cc1Br
Agent: CCN=C=NCCCN(C)C
Product: COc1cc2[nH]c(C(=O)N3CCN(c4ncccc4NC(C)C)CC3)cc2cc1Br

Procedure:
Following the general procedure of EXAMPLE 16A and making non-critical variations but starting with 5-bromo-6-methoxyindole-2-carboxylic acid (PREPARATION 82, 0.40 g), 1-[3-(1-methylethylamino)-2-pyridinyl]piperazine (0.33 g) and 1-(ethyl)-3-(dimethylaminopropyl)carbodiimide (0.34 g), the title compound is obtained, mp 202°-204°.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:15](=[NH:17])[NH2:16])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:25][C:26](=O)[CH3:27]>C(Cl)Cl>[Br:1][C:2]1[S:3][C:4]([C:15]2[NH:16][CH:25]=[C:26]([CH3:27])[N:17]=2)=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])[N:6]=1
Reactant: CC(=O)CCl
Reactant: N=C(N)c1sc(Br)nc1-c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1c[nH]c(-c2sc(Br)nc2-c2ccc(Cl)cc2Cl)n1
Reaction time: 4 h
Yield: 72 %

Procedure:
To a solution of 2-bromo-4-(2,4-dichlorophenyl)-1,3-thiazole-5-carboximidamide (70 mg, 0.2 mmol) in DCM (4 mL) was added potassium carbonate (82.7 mg, 0.598 mmol) followed by solution of chloroacetone (50 uL, 0.6 mmol) in DCM (0.4 mL). The mixture was heated to reflux for 3 hours, at which time LCMS indicated ˜50% conversion. Additional cloroacetone (11 ul) and K2CO3 (19 mg) were added and heating was continued for additional 4 hours. LCMS showed complete conversion. Solvent was removed under reduced pressure and the residue was purified using ISCO chromatography, 20%-60% ethyl acetate in hexane to afford the title compound (56 mg, 70%). LCMS: (FA) ES+, 388, 390, 392. 1H NMR (400 MHz, d1-chloroform) δ: 7.60 (dd, J=5.37, 1.71 Hz, 1H), 7.45-7.40 (m, 3H), 2.23 (s, 3H).
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].C(O)CCC>C(#N)C>[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: CCCCO
Solvent: CC#N
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 96.2 %

Procedure:
Fluvastatin methyl ester (2.0 g) was added to a mixture of NaOH (1 eq.) and butan-1-ol (15 ml). The mixture was stirred at about 80° C. for 2.5 h, after which the starting material was not detected by HPLC. Then, 40 ml of acetonitrile was dripped into the solution. The mixture was then cooled slowly to room temperature and stirred overnight. The product was isolated by filtration under nitrogen, washed with acetonitrile (45 ml) and dried at 50° C. in a vacuum oven for 24 h to obtain 1.96 g (96.2%) of fluvastatin sodium Form VII.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:24][C:25](=[O:33])[CH:26]([NH:31][CH3:32])[CH2:27][CH:28]([CH3:30])[CH3:29])[C:17](=[O:23])[NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Br)=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35].C(N(C(C)C)CC)(C)C>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:24][C:25](=[O:33])[CH:26]([N:31]([CH2:42][C:41]2[CH:44]=[CH:45][C:38]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:39][CH:40]=2)[CH3:32])[CH2:27][CH:28]([CH3:29])[CH3:30])[C:17](=[O:23])[NH:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: CNC(CC(C)C)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)CC(C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C)N(C)Cc1ccc(C(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 15 h
Yield: 40 %

Procedure:
2-(Methyl-amino)-4-methyl-pentanoic acid [2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide (0.5 mmol) was dissolved in THF (10 mL) and treated with 4-tert-butyl-benzyl bromide (0.75 mmol) and diisopropylethylamine (1.5 mmol). The reaction was stirred at 50° C. for 15 hours. Then the reaction mixture was allowed to cool to room temperature and concentrated to dryness. The residue was chromatographed on silica gel eluting with a gradient of 25% EtOAc/Hexanes to give the title compound with the yield of 40%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([C:16](=O)[CH2:17][CH3:18])[CH:6]([C:12](=O)[CH2:13][CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].[BrH:21].[NH:22]([C:24]1[NH:25][CH2:26][CH2:27][N:28]=1)[NH2:23].C(O)(C)C.C(OCC)C>C(OCC)C>[BrH:21].[C:4]([C:5]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:12]([CH2:13][CH3:14])[N:23]([NH:22][C:24]2[NH:28][CH2:27][CH2:26][N:25]=2)[C:16]=1[CH2:17][CH3:18])([O:3][CH2:1][CH3:2])=[O:20]
Reactant: NNC1=NCCN1
Reactant: CCOC(=O)C(C(=O)CC)C(C(=O)CC)C(=O)OCC
Agent: Br
Solvent: CC(C)O
Solvent: CCOCC
Product: CCOC(=O)c1c(C(=O)OCC)c(CC)n(NC2=NCCN2)c1CC

Procedure:
The compound is obtained following substantially the method described in Example 3, by reacting 13 g. (0.0455 mole) of diethyl-2,3-dipropionyl-succinate with 8.14 g. (0.0449 mole) of 2-hydrazino-4,5-dihydro-1H-imidazole hydrobromide. Yield 55 g. M.p. 181°-2°C (from isopropanol/diethyl ether). The free base melts at 155°C (from diethyl ether).