Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:33])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=1>C(#N)C>[Br:1][C:2]1[C:3]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:33])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[CH:25]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: NCCCCNC(=O)c1cccc([N+](=O)[O-])c1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(NCCCCNc1nc(Cl)ncc1Br)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 502 mg (2.2 mmol) of 5-bromo-2,4-dichloro-pyrimidine and 0.4 ml of triethylamine (2.3 mmol) in 2.5 ml of acetonitrile is mixed at 0° C. while being stirred with 547 mg (2.3 mmol) of N-(4-amino-butyl)-3-nitro-benzamide. The batch is stirred overnight at room temperature. The precipitate that is formed is suctioned off, washed with water and dried. 574 mg (1.3 mmol, corresponding to 61% of theory) of the product is obtained.
Reaction SMILES: [CH2:1]([C:17]1[C:22](=[O:23])[CH:21]=[C:20]([CH3:24])O[C:18]=1[CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl.[NH2:27][OH:28].C([O-])(=O)C.[Na+].O>C(O)C>[CH2:1]([C:17]1[C:22](=[O:23])[CH:21]=[C:20]([CH3:24])[N:27]([OH:28])[C:18]=1[CH3:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: NO
Reactant: CCCCCCCCCCCCCCCCc1c(C)oc(C)cc1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCc1c(C)n(O)c(C)cc1=O
Temperature: 25 °C

Procedure:
A mixture of 2 (200 mg, 0.57 mmol), hydroxylamine hydrochloride (399 mg, 5.7 mmol), sodium acetate (471 mg, 5.7 mmol), water (1 mL), and ethanol (2 mL) was heated at reflux for 3 days. After the reaction mixture was cooled to room temperature, the crude product was concentrated under diminished pressure to a yellow oil. The residue was purified by chromatography on a silica gel column. Elution with 5:1 chloroform/methanol gave 3-hexadecyl-1-hydroxy-2,6-dimethylpyridin-4(1H)-one (CPD-8) as a white solid: yield 0.088 g (42%); silica gel TLC Rf 0.5 (3:1 ethyl acetate/methanol); 1H NMR (CDCl3, 400 MHz) δ 0.83-0.85 (m, 3H), 1.22-1.27 (m, 28H), 2.32 (s, 3H), 2.46 (s, 3H), 2.55 (t, 2H, J=8 Hz) and 6.7 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([F:12])[CH:3]=1.CCOCC.C([Li])CCC.CON(C)[C:26]([C@H:28]1[CH2:32][CH2:31][CH2:30][N:29]1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:27]>C1COCC1>[F:12][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[C:8]([F:11])([F:10])[F:9])[C:26]([C@H:28]1[CH2:32][CH2:31][CH2:30][N:29]1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:27]
Reactant: Fc1cc(Br)ccc1C(F)(F)F
Reactant: CON(C)C(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)c1ccc(C(F)(F)F)c(F)c1
Temperature: -78 °C
Yield: 35 %

Procedure:
To a solution of 4-bromo-2-fluoro-1-(trifluoromethyl)benzene (4.854 g, 19.98 mmol) and ether (50 mL) cooled to −78° C. was added butyl lithium (7.990 mL, 19.98 mmol) slowly over 10 min. The reaction was transferred via cannula to a solution of 74 (4.30 g, 16.65 mmol) in THF (50 mL) cooled to −78° C. The reaction was stirred for 10 min after all aryl lithium was added. The reaction was quenched with water and extracted with DCM. The organic layer was concentrated and the crude product purified by SiO2 chromatography eluting with an EtOAc/hexane (1 to 5% EtOAc). A close running impurity was not removed by this purification. A SiO2 column was run eluting with an Et2O/hexane gradient (1 to 3% Et2O). The impurity was still present and the compound was finally purified on a SP4 reverse phase column chromatography eluting with MeCN/water gradient (65 to 100% MeCN) to afford 2.105 g (33.2%) of (R)-tert-butyl 2-(3-fluoro-4-(trifluoromethyl)benzoyl)-pyrrolidine-1-carboxylate (76).
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:18])=O>C(OCC)(=O)C>[Cl:18][CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1
Reactant: COCCCOc1ccnc(CO)c1C
Reactant: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: COCCCOc1ccnc(CCl)c1C
Yield: 112.8 %

Procedure:
2-Hydroxymethyl-4-(3-methoxypropoxy)-3-methylpyridine (5.0 g (23.7 mmol)) was dissolved in ethyl acetate (40 ml), and thionyl chloride (4.23 g (35.6 mmol)) was added dropwise into the solution in a temperature that did not exceed 25° C. Stirring was carried out at room temperature, and then after it had been confirmed by TLC that the starting material had disappeared, vacuum concentration was carried out, thus obtaining 2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine (6.14 g (yield: 97.4%)).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][OH:11])[C:5]([NH2:12])=[C:4]([Cl:13])[N:3]=1.[C:14]([O-])([O-])=[O:15].[K+].[K+].ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O>C(#N)C>[NH2:1][C:2]1[N:7]=[C:6]2[C:5]([NH:12][C:14](=[O:15])[N:8]2[CH2:9][CH2:10][OH:11])=[C:4]([Cl:13])[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1nc(Cl)c(N)c(NCCO)n1
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: [K+]
Solvent: CC#N
Product: Nc1nc(Cl)c2[nH]c(=O)n(CCO)c2n1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A mixture of 2-[(2,5-diamino-6-chloro-pyrimidin-4-yl)amino]ethanol obtained in step 1 (10.0 g, 49.26 mmol) in acetonitrile (400 ml) were cooled to 0° C. To this reaction mixture K2CO3 (20.39 gm, 147.7 mmol) and 4-nitrophenyl chloroformate (19.8 g, 98.52 mmol)was added and stirred at 25-27° C. for 24 hours. This reaction mixture was filtered and washed with acetonitrile (300 ml) and diethyl ether (300 ml) respectively. Solid obtained was dried to obtain crude 2-amino-6-chloro-9-(2-hydroxyethyl)-7H-purin-8-one as a yellow solid. Small amount of crude material was purified by column chromatography to obtain pure product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[S:9][CH:10]=1)=[O:5])[CH3:2].[CH3:17][C:18]([CH3:20])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH:11]2[CH2:16][CH2:15][N:14]([CH:18]([CH3:20])[CH3:17])[CH2:13][CH2:12]2)[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CC(C)=O
Reactant: CCOC(=O)c1csc(C2CCNCC2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)c1csc(C2CCN(C(C)C)CC2)n1
Temperature: 40 °C
Reaction time: 18 h
Yield: 81.1 %

Procedure:
A mixture of 2 g (8.3 mmol) 2-piperidin-4-yl-thiazole-4-carboxylic acid ethyl ester, 0.67 g acetone, 1.2 ml acetic acid and 2.47 g (11.6 mmol) sodium triacetoxyborohydride in 20 ml THF was stirred at 40° C. for 18 h. After evaporation to dryness the residue was extracted with 3×250 ml ethyl acetate and the combined organic phases were washed with 2×NaHCO3, NaCl aq., dried with MgSO4 and evaporated to yield 1.9 g (83%) of the title compound of orange solid. (m/e): 283.0 (MH+; 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([C:20]#[N:21])([CH3:19])[CH3:18])[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C(N(CC)CC)C.[Cl:30][C:31]1[N:36]=[C:35]2[S:37][C:38]([C:40](Cl)=[O:41])=[CH:39][C:34]2=[N:33][CH:32]=1>C(Cl)Cl>[Cl:30][C:31]1[N:36]=[C:35]2[S:37][C:38]([C:40]([NH:1][C:2]3[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([C:20]#[N:21])([CH3:19])[CH3:18])[CH:12]=4)[CH:5]=[CH:6][C:7]=3[CH3:8])=[O:41])=[CH:39][C:34]2=[N:33][CH:32]=1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1N
Reactant: O=C(Cl)c1cc2ncc(Cl)nc2s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2ncc(Cl)nc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of N-(3-amino-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide 5 (2.56 mmol, 750 mg) and triethylamine (12.78 mmol, 1.782 mL) in CH2Cl21 ml at 0° C. was added 3-chlorothieno[2,3-b]pyrazine-6-carbonyl chloride 94 in 1 mL CH2Cl2 and stirred at rt for 1 h. The reaction mixture was quenched with water, extracted with CH2Cl2 (2×). The organic layer was dried and concentrated under reduced pressure. Purified with column chromatography (10-20% ethyl acetate in CH2Cl2) gave 3-chloro-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 95 (1.04 g, 83%). NMR (400 MHz, DMSO-d6) 1.76 (s, 6H), 2.26 (s, 3H), 7.32 (d, J=8.2 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.64 (dd, J=8.2 Hz and 2.0 Hz, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.87 (d, J=2.3 Hz, 1H), 7.95 (d, J=7.8 Hz, 1H), 8.05 (s, 1H), 8.57 (s, 1H), 8.98 (s, 1H), 10.37 (s, 1H), 10.56 (s, 1H). (m/z)=490 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[CH3:14])=[O:5].[F:22][CH2:23][C:24](Cl)=[O:25]>>[F:22][CH2:23][C:24]([NH:1][C:2]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:8]=1[CH3:14])=[O:5])=[O:25]
Reactant: Cc1cccc(NC(=O)c2cc([N+](=O)[O-])ccc2N)c1C
Reactant: O=C(Cl)CF
Product: Cc1cccc(NC(=O)c2cc([N+](=O)[O-])ccc2NC(=O)CF)c1C
Yield: 87.2 %

Procedure:
3.6 g of N-(2-amino-5-nitrobenzoyl)-2,3-dimethylaniline and 1.82 g of fluoroacetyl chloride are treated in the same manner as described in Example 1-(1), whereby 3.8 g of N-(2-fluoroacetamido-5-nitrobenzoyl)-2,3-dimethylaniline are obtained as colorless needles.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][CH2:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)[CH2:3][CH2:2]1.[C:22]([NH:26][C:27](=[O:33])[CH2:28][CH2:29][C:30](O)=[O:31])([CH3:25])([CH3:24])[CH3:23].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[C:22]([NH:26][C:27](=[O:33])[CH2:28][CH2:29][C:30]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:8]3[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=3[CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)[CH2:3][CH2:2]1)=[O:31])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)NC(=O)CCC(=O)O
Reactant: c1ccc2c(c1)CCc1ccccc1N2C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)CCC(=O)N1CCC(N2c3ccccc3CCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
83.2 mg (0.299 mmol) of 5-(4-piperidinyl)-10,11-dihydro-5H-dibenzo[b,f]azepine, 62.2 mg (0.359 mmol) of 4-(t-butylamino)-4-oxobutanoic acid and 82.6 mg (0.431 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride were dissolved in 5 ml of dichloromethane. 0.06 ml (0.431 mmol) of triethylamine and 3.67 mg (0.03 mmol) of 4-dimethylaminopyridine were added to the obtained solution, and they were stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. Ethyl acetate was added thereto. After washing with 1 N aqueous hydrochloric acid solution, the organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (dichloromethane:methanol=9:1) to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=1.ClC1C=C(C=CC=1)C(OO)=[O:16]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[N+:4]([O-:16])[C:5]2[CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=1
Reactant: Brc1cnc2c(c1)CCC2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cc(Br)cc2c1CCC2
Temperature: 0 °C

Procedure:
A solution of 3-bromo-6,7-dihydro-5H-[1]pyrindine (4 gm) and 3-chloroperoxybenzoic acid (2 equiv.) in CHCl3 was refluxed for 3 hours. An additional equivalent of 3-chloroperoxybenzoic acid was added to the reaction and heating was continued for another hour. The reaction was then cooled to 0° C., filtered, and extracted into CH2Cl2 from 1:1 saturated NaHCO3 /NaHCO3 (using caution), dried over Na2SO4, filtered, and evaporated. The residue was chromatographed on silica gel using 10:1 hexane/ethyl acetate to remove remaining starting material, ethyl acetate to remove 3-chloroperoxybenzoic acid residues, and then 10% MeOH/CH2Cl2 to elute the final compound. The product yield was 2 gm. 1H NMR(CDCl3): d 8.20 (s, 1 H), 7.25 (s, 1 H), 3.10 (m, 4 H), 2.20 (m, 2 H).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:15]=[N:14][CH:13]=[C:12]2[NH:16][CH:17]=[CH:18][C:11]=12.[CH3:19][CH:20]([N:22]1[C:26]([C:27]([NH:29][C:30]2[C:31]3[C:35]([CH:36]=[C:37](B4OC(C)(C)CC(C)(C)O4)[CH:38]=2)=[N:34][N:33](C2CCCCO2)[CH:32]=3)=[O:28])=[CH:25][CH:24]=[N:23]1)[CH3:21].O>O1CCOCC1>[CH3:21][CH:20]([N:22]1[C:26]([C:27]([NH:29][C:30]2[CH:38]=[C:37]([C:10]3[CH:15]=[N:14][CH:13]=[C:12]4[NH:16][CH:17]=[CH:18][C:11]=34)[CH:36]=[C:35]3[C:31]=2[CH:32]=[N:33][NH:34]3)=[O:28])=[CH:25][CH:24]=[N:23]1)[CH3:19]
Reactant: CC(C)n1nccc1C(=O)Nc1cc(B2OC(C)(C)CC(C)(C)O2)cc2nn(C3CCCCO3)cc12
Reactant: Brc1cncc2[nH]ccc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)n1nccc1C(=O)Nc1cc(-c2cncc3[nH]ccc23)cc2[nH]ncc12
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A microwave vial was charged with Solvias catalyst (7 mg), tripotassium phosphate (84 mg) and 4-bromo-1H-pyrrolo[2,3-c]pyridine (from prep such as in US2005/0090529, 29 mg). 1-(1-methylethyl)-N-[2-(tetrahydro-2H-pyran-2-yl)-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-2H-indazol-4-yl]-1H-pyrazole-5-carboxamide (65 mg) in 1,4-dioxane (0.5 ml) was added, followed by water (0.1 ml) and the reaction was heated under microwave irradiation for a total of 30 min at 120° C. The reaction was washed through a silica cartridge preconditioned with methanol, with methanol. The solvent was removed under a stream of nitrogen, then washed with DCM and water. The resultant solution was evaporated under a stream of nitrogen. The residue was dissolved in DMSO:methanol (1 ml, 1:1, v/v) and purified by MDAP (method A). Appropriate fractions were dried under a stream of nitrogen. The residue was dissolved in methanol, 2M HCl (aq) (3 drops) was added and the solution was left to stand for 60 min. The solvent was removed under a stream of nitrogen and the residue was dissolved in methanol, washed with methanol through an aminopropyl cartridge preconditioned with methanol and dried under a stream of nitrogen to give title compound, 5 mg.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][C@H:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:48][C:49]1[S:50][CH:51]=[CH:52][N:53]=1>C(Cl)Cl>[CH:28]1([CH2:33][C@H:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:35]([NH:48][C:49]2[S:50][CH:51]=[CH:52][N:53]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Nc1nccs1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2nccs2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
A solution of triphenylphosphine (3.35 g, 12.79 mmol) in methylene chloride (19 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (2.28 g, 12.79 mmol) in small portions. The reaction mixture was stirred at 0° C. for 30 min, and during this time period, the color of the reaction mixture changed from light yellow to a darker yellow then to a purple color. The cooled purple reaction mixture was then treated with 3-cyclopentyl-2(R)-(4-methanesulfonylphenyl)propionic acid (prepared as in Example 128, 2.23 g, 7.52 mmol). The resulting reaction mixture was then allowed to warm to 25° C. over 45 min. The reaction mixture was then treated with 2-aminothiazole (1.88 g, 18.81 mmol). The resulting reaction mixture was stirred at 25° C. for 12 h. The reaction mixture was then concentrated in vacuo to remove methylene chloride. The remaining black residue was diluted with ethyl acetate (300 mL). The organic layer was washed sequentially with a 10% aqueous hydrochloric acid solution (2×100 mL), a 5% aqueous sodium bicarbonate solution (3×100 mL), and a saturated aqueous sodium chloride solution (1×200 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 9/1, 3/1, and then 11/9 hexanes/ethyl acetate) afforded 3-cyclopentyl-2(R)-(4-methanesulfonylphenyl)-N-thiazol-2-yl-propionamide (2.10 g, 74%) as a white foam: mp 78–80° C. (foam to gel); [α]23589=−70.4° (c=0.027, chloroform); EI-HRMS m/e calcd for C18H22N2O3S2 (M+) 378.1072, found 378.1081.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C@H:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[O:22])[C@@H:13]([CH3:31])[CH2:12]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.[C:41](Cl)(=[O:43])[CH3:42]>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([C:21](=[O:22])[C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[CH:13]([CH3:31])[CH2:12]2)[C:41](=[O:43])[CH3:42])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)Cl
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](Nc3ccc([N+](=O)[O-])cc3)C[C@@H]2C)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)N2c3ccccc3C(N(C(C)=O)c3ccc([N+](=O)[O-])cc3)CC2C)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (2S,4R)-[4-(4-nitro-phenylamino)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]-(4-methoxy-phenyl)-methanone (1.00 equiv.) in methylene chloride was added diisopropylethylamine (1.05 equiv) followed by acetyl chloride (1.00 equiv). The mixture was stirred at rt 48 h. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with sat. aqueous sodium bicarbonate, brine and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (25/75 hexanes/ethyl acetate gradient) to afford pure N-(4-nitro-phenyl)-N-[1-(4-methoxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide; which was reduced to N-(4-amino-phenyl)-N-[1-(4-methoxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide using excess NH4CO2H, catalyic Pt(sulfided), in ethanol at reflux for 30 m., followed by filtration and concentration. The amine was used without further purification due to inherent chemical instability.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[CH:7]=[CH:8][C:9]1[CH:14]=[N:13][CH:12]=[CH:11][N:10]=1.[CH3:19][NH:20][CH3:21].Cl>>[CH3:19][N:20]([CH3:21])[CH2:2][CH2:3][O:4][C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[CH:7]=[CH:8][C:9]1[CH:14]=[N:13][CH:12]=[CH:11][N:10]=1
Reactant: ClCCOc1ccccc1C=Cc1cnccn1
Reactant: CNC
Agent: Cl
Product: CN(C)CCOc1ccccc1C=Cc1cnccn1

Procedure:
2-[o-(β-Dimethylamino-ethoxy)-styryl]-pyrazine was prepared from 2-[o-(β-chloro-ethoxy)styryl]-pyrazine and dimethylamine, and the free base was converted into its monohydrochloride, yielding 54% of theory of the compound of the formula ##STR13## which had a melting point of 194°-195° C.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:28]([Cl:29])=[C:27]([O:30][CH3:31])[CH:26]=[C:25]([Cl:32])[C:4]=1[CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:33]/[C:34](=[CH:43]\[CH:44]=[C:45](/[CH3:48])\[CH:46]=O)/[C:35](/[CH3:42])=[CH:36]/[C:37]([O:39][CH2:40][CH3:41])=[O:38].C1OC1CC>C1(C)C=CC=CC=1>[Cl:2][C:3]1[C:28]([Cl:29])=[C:27]([O:30][CH3:31])[CH:26]=[C:25]([Cl:32])[C:4]=1/[CH:5]=[CH:48]/[C:45](/[CH3:46])=[CH:44]/[CH:43]=[C:34](\[F:33])/[C:35](/[CH3:42])=[CH:36]/[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: CCOC(=O)/C=C(C)/C(F)=C/C=C(\C)C=O
Reactant: COc1cc(Cl)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(Cl)c1Cl
Agent: CCC1CO1
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C(C)/C(F)=C/C=C(C)/C=C/c1c(Cl)cc(OC)c(Cl)c1Cl
Yield: 58 %

Procedure:
A mixture of 2.36 g. (9.54 mmol) of 2,3,6-trichloro-4-methoxybenzyl triphenylphosphonium chloride and 2.0 g. (8.93 mmol) of ethyl (E,Z,E)-4-fluoro-3,7-dimethyl-8-oxo-2,4,6-octatrienoate in 200 ml. of toluene and 150 ml. of 1,2-butylene oxide was heated at 85°-90° C. under argon for 18 hours. The mixture was worked up in the usual manner and the resulting crude product was filtered through 150 g. of silica gel. Elution with methylene chloride gave 2.48 g. of a yellow crystalline substance. Recrystallization of this material from methylene chloride-isopropyl ether yielded 2.21 g. (58% yield) of ethyl (E,Z,E,E)-9-(2,3,6-trichloro-4-methoxyphenyl)-4-fluoro-3,7-dimethyl-2,4,6,8-nonatetraenoate as yellow crystals, mp. 140°-142.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([OH:10])[C:6]=2[CH:11]=1.Cl.Cl[CH2:14][C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([O:10][CH2:14][C:15]3[N:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:6]=2[CH:11]=1
Reactant: Oc1noc2ccc(Br)cc12
Reactant: ClCc1ncccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1ccc2onc(OCc3ncccn3)c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 41.9 %

Procedure:
5-bromobenzo[d]isoxazol-3-ol (200 mg, 0.93 mmol), 2-(chloromethyl)pyrimidine hydrochloride (200 mg, 1.21 mmol) and cesium carbonate (1 g) were combined in 10 mL DMF and stirred at ambient temperature for two days. The reaction mixture was diluted with 60 mL ethyl acetate, washed with water and brine and evaporated under vacuum. Flash chromatographic purification on 12 g silica gel with 0-100% ethyl acetate in hexane gave O-alkylated product 5-bromo-3-(pyrimidin-2-ylmethoxy)benzo[d]isoxazole (120 mg, 0.39 mmol).
Reaction SMILES: [NH2:1][C@@H:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C>ClCCl>[CH2:22]([O:21][C:19]([CH2:18][NH:1][C@@H:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4])=[O:20])[CH3:23]
Reactant: N[C@@H](c1ccccc1)[C@H](O)c1ccccc1
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN[C@@H](c1ccccc1)[C@H](O)c1ccccc1
Temperature: 25 °C

Procedure:
(1R,2S)-2-amino-1,2-diphenylethanol (2.10 g) was dissolved in dichloromethane (30 ml) and stirred at room temperature. Ethyl bromoacetate (2.00 g), dissolved in dichloromethane (15 ml), was added to the solution. The mixture was stirred at room temperature for 7 days, and then triethylamine (1.5 ml) was added and stirred at room temperature for an additional day. After the spot of the starting material in TLC disappeared, dichloromethane was evaporated under reduced pressure. Benzene (100 ml) was added to the remaining residue, and the triethylamine hydrobromide salt was washed out with water. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solution was filtered and evaporated. The residue (2.60 g, 88%) was recrystallized from hexane (ca. 300 ml). The crystals deposited were collected and dried under reduced pressure. Yield 2.20 g (75%); mp 123°-125° C.; [α]D18 +2.4° (c 1.00, EtOH). IR (KBr): 3180, 1745, 765, 705 cm -1. 1H-NMR (CDCl3): 1.17 (t, 3H, J=7 Hz), 2.35 (bs, 2H), 3.16 (pseudo s, 2H), 3.98 (q, 2H, J=7 Hz), 4.15 (d, 1H, J=6 Hz), 4.76 (d, 1H, J=6 Hz), 7.20 (s, 10H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH:31]([CH3:33])[CH3:32]>>[CH:31]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1)([CH3:33])[CH3:32]
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Reactant: CC(C)Br
Product: CC(C)Oc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 2-Bromo-propane following the procedure of Example 478: MS (ESI) m/z 436.