Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5](Cl)=O.[Cl:8][C:9]1[C:10]([CH3:31])=[C:11]([CH2:15][NH:16][C:17]2[N:18]=[C:19]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[S:20][C:21]=2[C:22]([NH2:24])=[O:23])[CH:12]=[CH:13][CH:14]=1.[OH-].[Na+].Cl>COCCOC>[Cl:8][C:9]1[C:10]([CH3:31])=[C:11]([CH2:15][N:16]2[C:17]3[N:18]=[C:19]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)[S:20][C:21]=3[C:22](=[O:23])[N:24]=[C:5]2[CH2:4][CH2:3][O:2][CH3:1])[CH:12]=[CH:13][CH:14]=1
Reactant: COCCC(=O)Cl
Reactant: Cc1c(Cl)cccc1CNc1nc(N2CCOCC2)sc1C(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: COCCc1nc(=O)c2sc(N3CCOCC3)nc2n1Cc1cccc(Cl)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-methoxypropionyl chloride (66.8 mg, 0.545 mmol) in 1,2-Dimethoxyethane (DME) (400 μl) was added to a solution of 4-{[(3-chloro-2-methylphenyl)methyl]amino}-2-(4-morpholinyl)-1,3-thiazole-5-carboxamide (100 mg, 0.273 mmol) in 1,2-Dimethoxyethane (DME) (1000 μl). The mixture was stirred at room temperature overnight, then quenched with methanol and concentrated. To the residue was added methanol (1 mL) followed by 6N NaOH (1 equiv.). The mixture was stirred at room temperature for 3 h, neutralized (pH ˜8) with 6N HCl, and concentrated. The residue was partitioned between dichloromethane and water. The organic layer was dried (sodium sulfate), filtered, and concentrated. The crude product was purified by reversed-phase HPLC and the fractions were neutralized with sat. aq. sodium bicarbonate. The combined fractions were concentrated to remove acetonitrile and the remaining water was extracted with dichloromethane. The organic layer was dried (sodium sulfate), filtered, and concentrated to provide 4-[(3-chloro-2-methylphenyl)methyl]-5-[2-(methyloxy)ethyl]-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one. (14 mg, 12%); LC/MS: MS (ES+) m/e 435 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.44 (s, 3H), 2.80 (t, J=6.7 Hz, 2H), 3.19 (s, 3H), 3.52 (m, 4H), 3.62-3.72 (m, 6H), 5.57 (s, 2H), 6.51 (d, J=7.6 Hz, 1H), 7.16 (m, 1H), 7.39 (d, J=7.8 Hz, 1H).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:16][CH:17]([Br:19])[CH3:18])=[CH:10][C:11]=2[N+:13]([O-])=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>C(O)C.[Pt]=O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:16][CH:17]([Br:19])[CH3:18])=[CH:10][C:11]=2[NH2:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(CC(C)Br)cc([N+](=O)[O-])c21
Agent: O=[Pt]
Solvent: CCO
Product: CC(=O)N1CCc2cc(CC(C)Br)cc(N)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.1 %

Procedure:
To a solution of 1-acetyl-5-(2-bromopropyl)-7-nitroindoline (50 g) in ethanol (1.5 l) was added platinum oxide (2.5 g), and the mixture was stirred at room temperature for 4 hours under an atmosphere of hydrogen. After the catalyst was filtered off, the filtrate was evaporated under reduced pressure to give 45 g of 1-acetyl-7-amino-5-(2-bromopropyl)indoline.
Reaction SMILES: [Li+].[F:2][C:3]([F:22])([F:21])[C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]([O-:20])=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[N+:48]([C:51]1[CH:56]=[CH:55][C:54]([NH:57][CH:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)=[CH:53][C:52]=1[C:64]([F:67])([F:66])[F:65])([O-:50])=[O:49].C(N(C(C)C)CC)(C)C.[O-2].[Al+3].[O-2].[O-2].[Al+3]>CN(C)C=O.O1CCCC1>[N+:48]([C:51]1[CH:56]=[CH:55][C:54]([NH:57][CH:58]2[CH2:59][CH2:60][N:61]([C:18](=[O:20])[CH2:17][CH2:16][N:13]3[CH2:12][CH2:11][N:10]([C:7]4[CH:8]=[N:9][C:4]([C:3]([F:2])([F:22])[F:21])=[CH:5][CH:6]=4)[CH2:15][CH2:14]3)[CH2:62][CH2:63]2)=[CH:53][C:52]=1[C:64]([F:67])([F:65])[F:66])([O-:50])=[O:49]
Reactant: O=C([O-])CCN1CCN(c2ccc(C(F)(F)F)nc2)CC1
Reactant: O=[N+]([O-])c1ccc(NC2CCNCC2)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCN1CCN(c2ccc(C(F)(F)F)nc2)CC1)N1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reaction time: 4 h
Yield: 54 %

Procedure:
3-[4-(6-Trifluoromethyl-pyridin-3-yl)-piperazin-1-yl]-propionic acid lithium salt (15 mg; 0.05 mmol, prepared in accordance with Example 125) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (19 mg; 0.05 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (0.75 mL). A solution of (4-nitro-3-trifluoromethyl-phenyl)-piperidin-4-yl-amine hydrochloride (16 mg; 0.05 mmol, prepared in accordance with Example 8) in dimethylformamide (0.25 mL) and diisopropylethyl amine (25 μL; 0.15 mmol) are added and the reaction is then stirred. After 4 hours at room temperature, aluminium oxide (90 active basic) is added and stiffing is continued for 40 minutes. The solids are removed by filtration and the filtrate is concentrated under high vacuum. The obtained residue is purified by preparative HPLC to afford the desired compound (16 mg; 0.027 mmol). The structure was confirmed using Protocol I-D. Calculated mass=574; observed mass=575; HPLC retention time=1.42 min.
Reaction SMILES: OC1C=CC(CNC(=O)C2C=CC(NC3C4[N:18]([CH:27]=[CH:28]N=4)[C:19]([C:22]4[CH:23]=[N:24]N[CH:26]=4)=CN=3)=CC=2)=CC=1.[Br:33][C:34]1[N:39]2[CH:40]=[CH:41][N:42]=[C:38]2[C:37]([NH:43][C:44]2[CH:52]=[CH:51][C:47]([C:48]([OH:50])=O)=[CH:46][CH:45]=2)=[N:36][CH:35]=1.NCC1C=NC=CC=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[Br:33][C:34]1[N:39]2[CH:40]=[CH:41][N:42]=[C:38]2[C:37]([NH:43][C:44]2[CH:45]=[CH:46][C:47]([C:48]([NH:24][CH2:23][C:22]3[CH:19]=[N:18][CH:27]=[CH:28][CH:26]=3)=[O:50])=[CH:51][CH:52]=2)=[N:36][CH:35]=1
Reactant: O=C(O)c1ccc(Nc2ncc(Br)n3ccnc23)cc1
Reactant: O=C(NCc1ccc(O)cc1)c1ccc(Nc2ncc(-c3cn[nH]c3)n3ccnc23)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NCc1cccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cccnc1)c1ccc(Nc2ncc(Br)n3ccnc23)cc1

Procedure:
In the same way as described for Compound 90, step 3, using 4-(5-bromoimidazo[1,2-a]pyrazin-8-ylamino)benzoic acid (365 mg, 1.57 mmol), 3-aminomethylpyridine (0.16 mL, 1.57 mmol), N,N-diisopropylethylamine (0.42 mL, 2.35 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (715 mg, 1.9 mmol) and DMF (6 mL). The crude residue is purified using column chromatography, eluting with EtOAc followed by EtOAc:MeOH (95:5) then EtOAc:NH3 (7M in MeOH). The title amide is isolated as a solid.
Reaction SMILES: Cl.N[CH2:3][C:4]1[CH:9]=[C:8]([CH:10]([CH3:13])[CH2:11][CH3:12])[CH:7]=[C:6]([S:14]([CH3:17])(=[O:16])=[O:15])[C:5]=1[OH:18].C1N2CN3CN(C2)CN1C3.FC(F)(F)C(O)=[O:32]>>[CH:3]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:13])[CH2:11][CH3:12])[CH:7]=[C:6]([S:14]([CH3:17])(=[O:16])=[O:15])[C:5]=1[OH:18])=[O:32]
Reactant: CCC(C)c1cc(CN)c(O)c(S(C)(=O)=O)c1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Product: CCC(C)c1cc(C=O)c(O)c(S(C)(=O)=O)c1

Procedure:
0.48 g (0.0016 mol) of 2-aminomethyl-4-(1-methylpropyl)-6-methylsulfonylphenol hydrochloride is reacted with 0.22 g of hexamethylenetetramine in 3 ml of trifluoroacetic acid in analogy to Example 1. Melting point: 68°-70° C.
Reaction SMILES: C(CC([O-])=O)#N.C(O[CH:10]=[C:11]([C:17]#[N:18])[C:12](OCC)=[O:13])C.NC(=N)S.S(O)(O)(=O)=O.[CH3:28][S:29][C:30](=[NH:32])[NH2:31]>>[C:17]([C:11]1[C:12]([OH:13])=[N:31][C:30]([S:29][CH3:28])=[N:32][CH:10]=1)#[N:18]
Reactant: CSC(=N)N
Reactant: CCOC=C(C#N)C(=O)OCC
Agent: N#CCC(=O)[O-]
Agent: N=C(N)S
Agent: O=S(=O)(O)O
Product: CSc1ncc(C#N)c(O)n1

Procedure:
Scheme I describes a typical method for preparing the pyrido[2,3-d]pyrimidin-7(8H)-ones and the 7-(8H)-imides, compounds wherein X is O or NH. The synthesis starts by reacting a cyanoacetate such as ethyl ethoxymethylenecyanoacetate with a thiopseudourea such as 2-methyl-2-thiopseudourea sulfate to provide 5-cyano-4-hydroxy-2-(methylsulfanyl)pyrimidine. This reaction is described more fully in Helv. Chim. Acta., 42:763-772 (1959). The 4-hydroxypyrimidine is next reacted with a halogenating agent such as phosphorous oxychloride or thionyl chloride to provide a 4-halo pyrimidine, for example, 5-cyano-4-chloro-2-(methylsulfanyl)pyrimidine. The halopyrimidine next is reacted with an amine R2NH2 to provide a 5-cyano-4-substituted amino-2-(methylsulfanyl)pyrimidine. The amine utilized can have R2 be the group desired in the final product, for example, alkyl such as methyl, or R2 can be a group that can be later removed, for example, benzyl or the like, to generate compounds wherein R2 is hydrogen. Compounds where R2 is hydrogen can be alkylated and acylated by standard methods.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[S:25][C:16]=2[N:17]=[C:18]([C:20]2[O:24][N:23]=[CH:22][CH:21]=2)[N:19]=1>>[O:24]1[C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[CH:27]=[C:26]([C:28]([F:30])([F:31])[F:29])[S:25][C:16]=3[N:17]=2)=[CH:21][CH:22]=[N:23]1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3ccno3)nc2s1
Product: FC(F)(F)c1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(isoxazol-5-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-methylenedioxyphenethylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N:1]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])([CH2:3][C:4]([OH:6])=O)[CH3:2].C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[CH2:47]([O:49][C:50]([N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)=[O:51])[CH3:48].C([O-])(O)=O.[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH2:47]([O:49][C:50]([N:52]1[CH2:53][CH2:54][N:55]([C:4](=[O:6])[CH2:3][N:1]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH3:2])[CH2:56][CH2:57]1)=[O:51])[CH3:48]
Reactant: CCOC(=O)N1CCNCC1
Reactant: CN(CC(=O)O)C(=O)OCc1ccccc1
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)CN(C)C(=O)OCc2ccccc2)CC1
Reaction time: 12 h

Procedure:
To a solution of 500 mg Z-Sar-OH in 15 ml DMF were added 1.1 ml N-ethylmorpholine, 735 mg TOTU and 354 mg 1-ethoxycarbonylpiperazine. After stirring for 12 h, aqueous NaHCO3 was added and the reaction mixture was diluted with ethyl acetate and washed with aqueous LiCl (4%) and 0.1 M HCl. The crude product obtained after evaporation of the solvent was used without further purification. Yield: 830 mg.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[F:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[C:40]#[N:41])[O:36][CH2:35][CH2:34][C:33]2=O>C1COCC1>[F:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[C:40]#[N:41])[O:36][CH2:35][CH2:34]/[C:33]/2=[CH:2]\[O:3][CH3:4]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1cc2c(cc1F)C(=O)CCO2
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CO/C=C1\CCOc2cc(C#N)c(F)cc21
Temperature: -78 °C
Reaction time: 18 h

Procedure:
In a 250 ml, round bottom flask, (methoxymethyl) (triphenyl)phosphonium chloride (1.3 g, 3.8 mmol) was dissolved in THF (20 mL). The solution was cooled to −78° C. To above solution was added n-butyl lithium (0.49 mL, 2.50 M in Hexane, 1.05 mmol) dropwise. Reaction color changed to orange. The mixture was cooled to −78° C. and to it was added 6-Fluoro-4-oxo-3,4-dihydro-2H-chromene-7-carbonitrile (100 mg, 0.52 mmol). The reaction was let warm to RT and stirred at RT for 18 hours. The reaction was then quenched with addition of saturated ammonium chloride (5 mL) and extracted with dichloromethane. The organic phase was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by flash column chromatography (hexane/EtOAc 0-50%). The desired product was obtained. LC-MS (IE, m/z): 220.3 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH3:12][N:13]1C(=O)CCC1>[C-]#N.[C-]#N.[Zn+2].[Zn].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].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH3:11][C:8]1[C:7]2[NH:6][CH:5]=[CH:4][C:3]=2[C:2]([C:12]#[N:13])=[CH:10][CH:9]=1
Reactant: CN1CCCC1=O
Reactant: Cc1ccc(Br)c2cc[nH]c12
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1ccc(C#N)c2cc[nH]c12
Temperature: 140 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
To a solution of 306 (300 mg, 1.43 mmol) in NMP (3 mL) under argon atmosphere were added Zn(CN)2 (167 mg, 1.43 mmol), zinc powder (18 mg, 0.28 mmol), Pd2(dba)3 (198 mg, 0.21 mmol), and dppf (237 mg, 0.42 mmol). After stirring at 140° C. for 18 h, the mixture was cooled and partitioned between ethyl EtOAc (200 mL) and water (50 mL). The organic layer was separated, washed with brine, dried (MgSO4), filtered, and evaporated in vacuo. The residue was purified by SiO2 chromatography eluting with 15% EtOAc/petroleum ether to afford 222 mg (85%) of 7-methyl-1H-indole-4-carbonitrile (308) as yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[C:4]([CH3:17])=[CH:5][CH:6]=[N:7]2.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[OH:26].[OH-].[K+]>C(OCCO)C>[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[O:26][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[C:4]([CH3:17])=[CH:5][CH:6]=[N:7]2
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1Cl
Reactant: Oc1ccc(Cl)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCCO
Product: COc1cc([N+](=O)[O-])c2nccc(C)c2c1Oc1ccc(Cl)cc1Cl

Procedure:
The title compound was prepared from 5-chloro-6-methoxy-4-methyl-8-nitroquinoline from Example 1 (15 g, 0.06 mol), 2,4-dichlorophenol (38 g, 0.23 mol), potassium hydroxide (13.2 g, 0.24 mol) and 2-ethoxyethanol (150 mL) as described in Example 1. The yield was 14.5 g (64%), mp 165.5°-168°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:32][C:33]1[CH:34]=[C:35]([CH:40]=[CH:41][CH:42]=1)[C:36]([O:38]C)=[O:37])[S:9]([C:12]1[CH:17]=[C:16]([C:18]([NH:20][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH:22]2[CH3:30])=[O:19])[CH:15]=[CH:14][C:13]=1[Cl:31])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].O>C(#N)C.O>[C:1]([O:5][C:6]([N:8]([CH2:32][C:33]1[CH:34]=[C:35]([CH:40]=[CH:41][CH:42]=1)[C:36]([OH:38])=[O:37])[S:9]([C:12]1[CH:17]=[C:16]([C:18]([NH:20][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH:22]2[CH3:30])=[O:19])[CH:15]=[CH:14][C:13]=1[Cl:31])(=[O:10])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cccc(CN(C(=O)OC(C)(C)C)S(=O)(=O)c2cc(C(=O)NN3c4ccccc4CC3C)ccc2Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CC1Cc2ccccc2N1NC(=O)c1ccc(Cl)c(S(=O)(=O)N(Cc2cccc(C(=O)O)c2)C(=O)OC(C)(C)C)c1

Procedure:
Dissolve the compound obtained in Step B (1.14×10−3 mol) in an acetonitrile/water (40 ml/8 ml) mixture. Add lithium hydroxide (1.14×10−2 mol) and heat at 50° C. with stirring. After heating for 2 hours, the reaction mixture is poured into water (100 ml). Extract 3 times with ethyl acetate (50 ml). The organic phase is then washed with water and then with brine, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure.
Reaction SMILES: C[Al](C)C.[Br:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[CH2:9]C#N.Cl.C([O:19][CH2:20][CH3:21])(=O)C>C1(C)C=CC=CC=1>[Br:5][C:6]1[CH:7]=[C:8]([CH2:9][C:20](=[O:19])[CH3:21])[CH:12]=[CH:13][CH:14]=1
Reactant: N#CCc1cccc(Br)c1
Reactant: CCOC(C)=O
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)Cc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Trimethylaluminium in toluene (30 mL, 2M) was added to a -78° C. solution of m-bromobenzyl cyanide (3.92 g, 20 mmol) in toluene (20 mL) and the mixture was slowly warmed up and refluxed for 12 h. After being cooled to 0° C., the solution was carefully added to crushed ice and made acidic with 6N HCl. Ethyl acetate was added and the mixture was vigorously stirred for 1 h. The organic layer was washed with NaHCO3, brine and dried with MgSO4. Removal of the solvent left an oil (4.53 g) which was used as such in the next step.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[CH2:11]([C:18]1[S:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[C:19]=1[S:27](Cl)(=[O:29])=[O:28])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:27]([C:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[S:22][C:18]=1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:28])=[O:29]
Reactant: O=S(=O)(Cl)c1c(Cc2ccccc2)sc2ccccc12
Reactant: Cc1noc(N)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2c(Cc3ccccc3)sc3ccccc23)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-benzylbenzo[b]thiophene-3-sulfonamide was prepared by the method of Example 41 with 4-bromo-3-methyl-5-aminoisoxazole (1.0 mmoles, 0.177 g), NaH (2.5 mmoles, 100 mg), 2-benzylbenzo[b]thiophene-3-sulfonyl chloride (1.2 mmoles, 0.39 g) and THF (7 ml). Flash chromatography (5% methanol/chloroform) followed by recrystallization from chloroform and hexanes provided 0.11 g (24%) of a tan crystalline solid, m.p. 120-123° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([NH2:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH3:19][O:20][C:21]1[CH:31]=[CH:30][CH:29]=[C:23]2[C:24]([O:26][C:27](=O)[C:22]=12)=[O:25]>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[C:27](=[O:26])[C:22]3[C:23](=[CH:29][CH:30]=[CH:31][C:21]=3[O:20][CH3:19])[C:24]2=[O:25])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(N)CS(C)(=O)=O)ccc1OC
Reactant: COc1cccc2c1C(=O)OC2=O
Solvent: CC(=O)O
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(OC)c3C2=O)ccc1OC

Procedure:
2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-methoxyisoindoline-1,3-dione was prepared by the procedure of Example 8 from 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (580 mg, 2.12 mmol) and 3-methoxyphthalic anhydride (380 mg, 2.13 mmol) in acetic acid (15 mL). The product was obtained as a white solid (620 mg, 67% yield): mp, 162.5-164.5° C.; 1H NMR (CDCl3) δ 1.45 (t, J=6.9 Hz, 3H, CH3), 2.85 (s, 3H, CH3), 3.78 (dd, J=4.7, 10.5 Hz, 1H, CHH), 3.84 (s, 3H, CH3), 3.99 (s, 3H, CH3), 4.09 (q, J=6.9 Hz, 2H, CH2), 4.54 (dd, J=10.3, 14.4 Hz, 1H, CHH), 5.87 (dd, J=4.6, 10.7 Hz, 1H, NCH), 6.80-6.83 (m, 1H, Ar), 7.10-7.18 (m, 3H, Ar), 7.38 (d, J=7.3 Hz, 1H, Ar), 7.63 (dd, J=7.5, 8.2 Hz, 1H, Ar); 13C NMR (CDCl3) δ 14.57, 41.32, 48.52, 54.62, 55.82, 56.19, 64.38, 111.35, 112.52, 115.56, 116.75, 117.58, 120.40, 129.58, 133.59, 136.30, 148.41, 149.46, 156.74, 166.43, 167.35; Anal Calcd for C21H23NO7S: C, 58.19; H, 5.35; N, 3.23. Found: C, 58.05; H, 5.35; N, 3.24.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]=O.[OH-].[Na+].O>C(O)C>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1/[CH:17]=[CH:10]/[C:9](=[O:11])/[CH:8]=[CH:7]/[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cccs1
Reactant: CC(=O)/C=C/c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(/C=C/c1ccccc1)/C=C/c1cccs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.2 %

Procedure:
A mixture of 65.1 g (0.45 mol) of E-4-phenyl-3-buten-2-one, 50 g (0.45 mol) of 2-thiophenecarboxaldehyde, 4 mL of aqueous 10% sodium hydroxide, 50 mL of water, and 75 mL of ethanol was stirred at ambient temperature for 15 hours. The solid which separated was collected by filtration and air dried to give 85.6 g (80% yield) of E,E-1-(2-thienyl)-5-phenyl-1,4-pentadien-3-one as a yellow solid. 1H NMR, IR, and FDMS analyses were consistent with the expected structure.
Reaction SMILES: [S:1]1C=C[CH:3]=[C:2]1[CH:6]=[O:7].[F:8][C:9]1[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=1[CH2:11][O:12][C:13]([CH3:18])([CH2:16]O)CO>C1C=CC=CC=1>[F:8][C:9]1[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=1[CH2:11][O:12][C:13]1([CH3:18])[S:1][CH:2]([CH:6]2[O:7][CH2:3][CH2:2][CH2:6][O:7]2)[CH:3]=[CH:16]1
Reactant: CC(CO)(CO)OCc1ccccc1F
Reactant: O=Cc1cccs1
Solvent: c1ccccc1
Product: CC1(OCc2ccccc2F)C=CC(C2OCCCO2)S1

Procedure:
Using the procedure of Example 51, thiophene-2-carboxaldehyde and 2-(2-fluorobenzyloxy)-2-methyl-1,3-propanediol were reacted, using benzene as solvent, to give, after separation by column chromatograph, c-5-(2-fluorobenzyloxy)-5-methyl-r-2-thienyl-1,3-dioxane, m.p. 111°-112°, and t-5-(2-fluorobenzyloxy)-5-methyl-r-2-thienyl-1,3-dioxane, m.p. 84°-85°.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]([N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][N:17]3[CH:25]=[CH:26][CH:27]=[C:16]3[CH2:15]2)=[O:13])=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C.[F:38][C:39]1[CH:40]=[CH:41][C:42]([CH3:48])=[C:43]([CH:47]=1)[C:44](Cl)=[O:45]>ClCCl>[CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][N:5]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([N:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][N:17]3[CH:25]=[CH:26][CH:27]=[C:16]3[CH2:15]2)=[O:13])=[CH:10][N:11]=1)[C:44](=[O:45])[C:43]1[CH:47]=[C:39]([F:38])[CH:40]=[CH:41][C:42]=1[CH3:48]
Reactant: CN(C)CCNc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cn1
Reactant: Cc1ccc(F)cc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)cc1C(=O)N(CCN(C)C)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.3 %

Procedure:
To a solution of 0.75 g of 10-[[6-[2- (dimethylamino) ethylamino]-3-pyridinyl]carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 5 ml of diisopropylethylamine in 75 ml of dichloromethane is added (slowly) 0.35 g of 5-fluoro-2-methylbenzoyl chloride in 10 ml of dichloromethane. The mixture is stirred at room temperature for 16 hours and the solution washed well with water. The organic layer is dried (MgSO4) and the solvent removed under vacuum. The residue is purified by column chromatography on silica gel with 30% methanol in chloroform as eluent to give 0.80 g of yellow solid; mass spectrum (CI), 511 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]([OH:13])=O.[F:14][C:15]([F:28])([F:27])[C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[NH2:19].P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[F:14][C:15]([F:27])([F:28])[C:16]1[CH:17]=[C:18]([NH:19][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([OH:1])=[C:3]([C:11]([NH:19][C:18]3[CH:20]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:22]=[C:16]([C:15]([F:14])([F:27])[F:28])[CH:17]=3)=[O:13])[CH:4]=2)[CH:20]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:22]=1
Reactant: O=C(O)c1ccc(O)c(C(=O)O)c1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClP(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 25 %

Procedure:
Using 4-hydroxyisophthalic acid (182 mg, 1 mmol), 3,5-bis(trifluoromethyl)-aniline (687 mg, 3 mmol), phosphorus trichloride (87 μl; 1 mmol) and toluene (10 mL), the same operation as the example 16 gave the title compound (151 mg, 25.0%) as a white crystal.