Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+].[Br:71][C:72]1[CH:77]=[C:76]([O:78][CH3:79])[C:75](I)=[CH:74][C:73]=1[F:81]>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH2:9]([S:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:75]2[CH:74]=[C:73]([F:81])[C:72]([Br:71])=[CH:77][C:76]=2[O:78][CH3:79])=[C:3](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1N
Reactant: COc1cc(Br)c(F)cc1I
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1Nc1cc(F)c(Br)cc1OC
Temperature: 130 °C
Yield: 48.6 %

Procedure:
A screw cap vial was charged with (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (0.500 g, 1.595 mmol), xantphos (0.185 g, 0.319 mmol), Pd2(dba)3 (0.146 g, 0.160 mmol), sodium tert-butoxide (0.153 g, 1.595 mmol) and toluene (7.98 ml). The vial was purged with Argon, sealed and heated to 130° C. for 10 minutes. The reaction was cooled to RT and 1-bromo-2-fluoro-4-iodo-5-methoxybenzene (0.581 g, 1.755 mmol) was added and the reaction was continued heating at 100° C. for an additional 30 minutes. The reaction was cooled to RT, diluted with water and extracted with DCM (3×). The combined organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The resulting material was concentrated, dissolved in minimal DCM and purified via column chromatography (silica gel 40 g, gradient elution 0 to 50% EtOAc:Heptane) to afford 0.40 g of (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl)acrylate (0.400 g, 0.775 mmol, 48.6% yield). m/z (ESI) 471.0
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]([NH:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=1[CH3:20])=[O:8].[K].CC(C)([O-])C.O>CN(C=O)C>[CH3:20][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:10]=1[N:9]1[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1=[O:8])[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1ccc(NC(=O)OCCCCCl)c(C)c1
Agent: CC(C)(C)[O-]
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(N2CCCCOC2=O)c(C)c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
300 mg (1.00 mmol) methyl 4-(N-[4-chlorobutoxycarbonyl]-amino)-3-methyl-benzoate are dissolved in 10 ml DMF combined with 168 mg (1.50 mmol) potassium-tert.-butoxide and stirred for 3 hours at 60° C. The reaction mixture is mixed with water and extracted 3 times with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated down i. vac. Then the residue is purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate 3:2).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.O[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][C:24]3[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=3)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Cc1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(-c2ccc(C(=O)Oc3ccc(C=O)cc3)cc2)cc1
Reaction time: 18 h
Yield: 40.4 %

Procedure:
Prepared using General Procedure 2: To a stirred solution of 4′-methyl-[1,1′-biphenyl]-4-carboxylic acid (0.5 g, 2.35 mmol) in DCM (10 mL) was added DMF (3 drops) then oxalyl chloride (0.262 mL, 3.1 mmol) and left for 2 h. The reaction mixture was added to a solution of 4-hydroxybenzaldehyde (0.31 g, 2.6 mmol) and TEA (0.4 mL, 2.82 mmol) in DCM (10 mL) and stirred for 18 h. The reaction mixture was diluted with DCM (100 mL) and washed with NaHCO3 (100 mL). The organic layer was pre-absorbed onto silica gel and then purified by chromatography (EA/isohexanes) to afford 300 mg (40%) 4-formylphenyl 4′-methyl-[1,1′-biphenyl]-4-carboxylate INT-27 as a white solid. LCMS-ESI (m/z) calculated for C21H16O3: 316; no m/z observed, tR=4.25 min (Method 1).
Reaction SMILES: ClC1C(CCCl)=C(C2C=CC=C(OC)C=2)N=C(N2CCOCC2)N=1.CC1C=C(N)C2C(=CC=CC=2)N=1.C[O:38][C:39]1[CH:40]=[C:41]([C:45]2[C:46]3[CH2:59][CH2:58][N:57]([C:60]4[C:69]5[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=5)[N:63]=[C:62]([CH3:70])[CH:61]=4)[C:47]=3[N:48]=[C:49]([N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)[N:50]=2)[CH:42]=[CH:43][CH:44]=1>>[CH3:70][C:62]1[CH:61]=[C:60]([N:57]2[C:47]3[N:48]=[C:49]([N:51]4[CH2:52][CH2:53][O:54][CH2:55][CH2:56]4)[N:50]=[C:45]([C:41]4[CH:40]=[C:39]([OH:38])[CH:44]=[CH:43][CH:42]=4)[C:46]=3[CH2:59][CH2:58]2)[C:69]2[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=2)[N:63]=1
Reactant: COc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2cc(C)nc3ccccc23)c1
Agent: COc1cccc(-c2nc(N3CCOCC3)nc(Cl)c2CCCl)c1
Agent: Cc1cc(N)c2ccccc2n1
Product: Cc1cc(N2CCc3c(-c4cccc(O)c4)nc(N4CCOCC4)nc32)c2ccccc2n1

Procedure:
In the same manner as Example 1-A-01, from 4-[4-chloro-5-(2-chloroethyl)-6-(3-methoxyphenyl)-pyrimidin-2-yl]-morpholine and 2-methyl-quinolin-4-ylamine, 4-[4-(3-methoxy-phenyl)-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-2-methyl-quinoline was obtained, and subsequently, further in the same manner as Example 1-A-09, the desired compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[N:7]([NH:12][CH3:13])[C:8]([CH3:11])=[CH:9][CH:10]=1)=[O:5].C(=O)(O)[O-].[Na+].[Br:23][CH2:24][C:25](Br)=[O:26]>ClCCl>[CH3:13][N:12]([N:7]1[C:8]([CH3:11])=[CH:9][CH:10]=[C:6]1[C:4](=[O:5])[C:3]1[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=1[Cl:1])[C:25](=[O:26])[CH2:24][Br:23]
Reactant: O=C(Br)CBr
Reactant: CNn1c(C)ccc1C(=O)c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(C(=O)c2ccccc2Cl)n1N(C)C(=O)CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
A stirred slurry of 2-(2-chlorobenzoyl)-1-methylamino-5-methylpyrrole (18.7 g, 75 mmol) and sodium bicarbonate (14.2 g, 170 mmol) in 100 ml of dichloromethane was treated with a solution of bromoacetyl bromide (15.2 g, 90 mmol) in 30 ml of dichloromethane over 30 minutes and stirred at room temperature overnight. The reaction mixture was quenched with 100 ml of H2O, separated, washed with H2O and brine, dried (MgSO4), filtered, and evaporated. The resultant oil was purified by HPLC (silica, 1:1 ethyl actate-hexane) to give an oil which crystallized from ether to give 22.7 g (82%) of needles, m.p. 108°-109°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([N:15]([CH3:17])[CH3:16])=[N:11][N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.[H-].[Na+].IC.[C:22](O)(=O)C>O1CCCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:22])[C:10]([N:15]([CH3:17])[CH3:16])=[N:11][N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1
Reactant: CN(C)C(=N[N+](=O)[O-])NCc1ccc(Cl)nc1
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CN(C)C(=N[N+](=O)[O-])N(C)Cc1ccc(Cl)nc1
Reaction time: 0.5 h

Procedure:
To a mixture of 0.24 g of 1-(6-chloro-3-pyridylmethyl)-3,3-dimethyl-2-nitroguanidine (Compound No. 6) and 6 ml of dry tetrahydrofuran (THF) was added 0.045 g of 60% sodium hydride (in mineral oil) at room temperature, followed by stirring for 30 minutes. A solution of 0.16 g of iodomethane in 1 ml of THF was added to the reaction mixture and allowed to react for 3 days. After adding 0.1 ml of acetic acid, the mixture was filtered to remove insoluble materials and the filtrate was concentrated. The residue was purified by a column chromatography [developing solvent: dichloromethanemethanol (20:1)] to obtain 0.17 g of 1-(6-chloro-3-pyridylmethyl)-1,3,3-trimethyl-2-nitroguanidine (Compound No. 14) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:24]=[CH:23][C:6]2[C:7]([NH:16][CH:17]([CH3:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[N:8][C:9]3[CH:10]=[CH:11][NH:12][C:13](=[O:15])[C:14]=3[C:5]=2[CH:4]=1)#[CH:2].[CH2:25]([N:32]=[N+:33]=[N-:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C.CO.[Cu]I>[CH2:25]([N:32]1[CH:2]=[C:1]([C:3]2[CH:24]=[CH:23][C:6]3[C:7]([NH:16][CH:17]([CH3:22])[C:18]([CH3:20])([CH3:19])[CH3:21])=[N:8][C:9]4[CH:10]=[CH:11][NH:12][C:13](=[O:15])[C:14]=4[C:5]=3[CH:4]=2)[N:34]=[N:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C#Cc1ccc2c(NC(C)C(C)(C)C)nc3cc[nH]c(=O)c3c2c1
Reactant: [N-]=[N+]=NCc1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CO
Product: CC(Nc1nc2cc[nH]c(=O)c2c2cc(-c3cn(Cc4ccccc4)nn3)ccc12)C(C)(C)C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
9-ethynyl-6-[(1,2,2-trimethylpropyl)amino]benzo[c]-1,6-naphthyridin-1(2H)-one (150 mg, 0.47 mmol) was dissolved in DMF/MeOH (2 mL) in a sealed tube. To the solution was added CuI (5.0 mg, 0.020 mmol) and Bn—N3 (310 mg, 2.4 mmol) under an argon atmosphere. The mixture was stirred at 100° C. for 8 h, then the resulting solution was filtered and purified by reverse phase HPLC to afford 9-(1-benzyl-1H-1,2,3-triazol-4-yl)-6-[(1,2,2-trimethylpropyl)amino]benzo[c]-1,6-naphthyridin-1(2H)-one. 1H NMR (400 MHz, MeOD) δ 10.30 (s, 1H), 8.64 (m, 2H), 8.30 (d, J=8.4 Hz, 1H), 7.65 (d, J=6.8 Hz, 1H), 7.40 (m, 5H), 6.93 (d, J=7.2 Hz, 1H), 5.70 (s, 2H), 4.46 (m, 1H), 1.46 (d, J=6.8 Hz, 3H), 1.09 (s, 9H). LRMS calculated for C27H28N6O [M+H]+, 453; found 454.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]([C:5]1[C:6]([CH2:16][CH2:17][C@@H:18]([OH:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:7][C:8]2[N:9]([C:11]([CH3:15])=[C:12]([CH3:14])[N:13]=2)[CH:10]=1)=[O:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+].ClCCl.C1C[O:53]CC1>>[CH3:26][N:2]([CH3:1])[C:3]([C:5]1[C:6]([CH2:16][CH2:17][C@@H:18]([OH:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:7]([OH:53])[C:8]2[N:9]([C:11]([CH3:15])=[C:12]([CH3:14])[N:13]=2)[CH:10]=1)=[O:4]
Reactant: C1CCOC1
Reactant: Cc1nc2cc(CC[C@@H](O)c3ccccc3)c(C(=O)N(C)C)cn2c1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: ClCCl
Product: Cc1nc2c(O)c(CC[C@@H](O)c3ccccc3)c(C(=O)N(C)C)cn2c1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 86 %

Procedure:
In a flame-dried flask filled with argon, the silyl ether 8-[dimethyl-1,1,2-trimethyl-propyl)-silanyloxy]-7-[(3R)-3-hydroxy-3-phenyl-propyl]-2,3-dimethyl-imidazo[1,2-a]pyridine-6-carboxylic acid dimethylamide (2.10 g, 4.1 mmol, sample contained 6 mol-% of the (3S)-enantiomer) was dissolved in dry THF (30 ml). At room temperature, a solution of tetrabutylammonium fluoride in THF (1 M, 420 ml, 4.2 mmol) was added slowly. A brown solution was obtained, which was stirred for 5 hours at room temperature. The reaction mixture was poured onto a mixture of saturated ammonium chloride solution (30 ml) and dichloromethane (50 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (3×15 ml). The combined organic phases were washed with water (20 ml), dried over sodium sulfate, and concentrated under reduced pressure. A grey solid (2.6 g) remained which was treated with a mixture of acetone (I ml) and diethyl ether (10 ml). The suspension was filtered, the residue was washed with diethyl ether and dried in vacuo. This afforded 1.6 g of the title compound still containing traces of impurities. After crystallization from ethyl acetate (100 ml) and isopropanol (10 ml), the spectroscopically pure title compound (1.3 g, 86% yield) was obtained as a grey crystalline solid. The optical purity was confirmed by capillary electrophoresis (85.2% ee).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([OH:10])[CH2:7][N:6]1[S:11](=[O:24])(=[O:23])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[C:15]([Cl:21])[C:14]=1[CH3:22])=[O:4].Cl>[OH-].[Na+]>[Cl:21][C:15]1[C:14]([CH3:22])=[C:13]([NH:12][S:11]([N:6]2[CH2:7][C@@H:8]([OH:10])[CH2:9][C@H:5]2[C:3]([OH:4])=[O:2])(=[O:23])=[O:24])[CH:18]=[CH:17][C:16]=1[C:19]#[N:20]
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1S(=O)(=O)Nc1ccc(C#N)c(Cl)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(NS(=O)(=O)N2C[C@@H](O)C[C@H]2C(=O)O)ccc(C#N)c1Cl
Yield: 100.8 %

Procedure:
A solution of 4A (60 mg, 0.160 mmol) in 4 mL of 1.6 N NaOH was stirred at rt for 1 h. The reaction mixture was acidified to pH 2 with 10% HCl. A solid precipitated which was filtered, washed with water and dried to afford the title compound (58 mg) as an orange solid. 1H NMR (CD3OD) δ 2.38-2.42 (m, 5H) 3.31-3.34 (m, 1H), 3.62-3.65 (m, 1H), 4.40-4.42 (m, 1H), 4.49-4.52 (m, 1H), 7.60 (d, 8.8, 1H), 7.71 (d, J=8.8, 1H); 13C NMR (CD3OD) δ 15.28, 39.89, 57.29, 61.95, 71.03, 109.61, 117.42, 121.42, 130.55, 132.93, 137.84, 143.77, 175.99; HPLC a) column: Phenominex ODS C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA; 1 min hold, 4 mL/min UV detection at 220 nm, 2.40 min retention time; HPLC b) column: Shimadzu Shim-Pack VP-ODS C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold; 4 mL/min, UV detection at 220 nm, 2.23 min retention time (63%); MS (ES) m/z 360 [M+H]+.
Reaction SMILES: [Cl-].[OH:2][NH3+:3].C(=O)([O-])[O-].[K+].[K+].[C:10]1([C:16](=[CH:19][CH2:20][CH3:21])[CH:17]=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[C:10]1([C:16](=[CH:19][CH2:20][CH3:21])[CH:17]=[N:3][OH:2])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCC=C(C=O)c1ccccc1
Reactant: [NH3+]O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCO
Product: CCC=C(C=NO)c1ccccc1
Reaction time: 2 h
Yield: 75.3 %

Procedure:
A mixture of hydroxylammonium chloride (10.84 g, 0.156 mol) and potassium carbonate (21.56 g, 156 mmol) in absolute ethanol (100 ml) was stirred for 2 h. The precipitated sodium chloride was filtered off and 2-phenyl-2-pentenal (5.00 g, 31 mmol) was added to the filtrate. The mixture was stirred at ambient temperature for 16 h. The solvent was evaporated in vacuo, the residue was crystallised from aqueous ethanol to give 4.09 g 2-phenyl-2-pentenal oxime.
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([OH:43])=O)=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[O:48]1[C:52]2[CH:53]=[CH:54][C:55]([CH2:57][NH2:58])=[CH:56][C:51]=2[O:50][CH2:49]1>>[O:48]1[C:52]2[CH:53]=[CH:54][C:55]([CH2:57][NH:58][C:41]([C:39]3[S:40][C:36]([N:33]4[CH2:34][CH2:35][N:31]([CH2:30][C:29]5[CH:28]=[CH:27][C:26]([F:25])=[CH:47][CH:46]=5)[C:32]4=[O:45])=[CH:37][C:38]=3[CH3:44])=[O:43])=[CH:56][C:51]=2[O:50][CH2:49]1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: NCc1ccc2c(c1)OCO2
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1ccc2c(c1)OCO2
Yield: 82 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with benzo[d][1,3]dioxol-5-ylmethanamine, the title compound was obtained as a colorless solid in 82% yield: 1H NMR (300 MHz, CDCl3) δ 7.30-7.23 (m, 2H), 7.07-6.98 (m, 2H), 6.85-6.73 (m, 3H), 6.09 (s, 1H), 5.95 (s, 2H), 5.92 (t, J=5.5 Hz, 1H), 4.46 (d, J=5.5 Hz, 2H), 4.42 (s, 2H), 3.84-3.76 (m, 2H), 3.48-3.40 (m, 2H), 2.49 (s, 3H); MS (ES+) m/z 468.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[N:6]=[C:7]([NH:10][C@H:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13][CH2:12]3)[O:8][CH2:9][C:4]=2[CH:3]=1.[CH2:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.[Pd]>[C@H:11]1([NH:10][C:7]2[O:8][CH2:9][C:4]3[CH:3]=[C:2](/[CH:22]=[CH:23]/[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:21]=[CH:20][C:5]=3[N:6]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1
Reactant: C=Cc1ccccc1
Reactant: Brc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C(=C/c1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2)\c1ccccc1
Yield: 16 %

Procedure:
A stirred mixture of (6-bromo-4H-benzo[d][1,3]oxazin-2-yl)-(R)-indan-1-yl-amine (Example 32) (200 mg, 0.58 mmol), styrene (91 mg, 0.87 mmol), tri(o-tolyl)phosphine (14.2 mg, 0.047 mmol), triethylamine (295 mg, 2.91 mmol) and palladium actetate (5.23 mg, 0.023 mmol) in acetonitrile (5 ml) was heated under reflux conditions for 23 h, evaporated and purified by flash chromatography (ethyl acetate/heptane) on silica gel and crystallization (dichloromethane/heptane) to yield the title compound as white solid (34 mg, 16%). MS (ISP): m/e=367.2 (M+H+); m.p. 162° C.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][CH2:7][C@H:8]2[CH2:13][C@@H:12]([C:14]3[O:18][NH:17][C:16](=[O:19])[CH:15]=3)[CH2:11][CH2:10][N:9]2C(OC)=O)=[CH:4][CH:3]=1.Br>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C@H:8]2[CH2:13][C@@H:12]([C:14]3[O:18][NH:17][C:16](=[O:19])[CH:15]=3)[CH2:11][CH2:10][NH:9]2)=[CH:24][CH:25]=1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1CCc1ccc(F)cc1
Agent: Br
Product: O=c1cc([C@H]2CCN[C@@H](CCc3ccc(F)cc3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.8 %

Procedure:
(2S,4S)-Methyl 2-(4-fluorophenethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (435 mg, 1.25 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 9.84 mL, 56.19 mmol) to give a yellow solution. The mixture was stirred at room temperature for 16 h, the solvent was removed and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2S,4S)-2-(4-fluorophenethyl)piperidin-4-yl)isoxazol-3(2H)-one (228 mg, 63%). 1H NMR (400 MHz, cd3od) δ 1.48 (dd, 1H), 1.64-1.97 (m, 3H), 2.13 (d, 1H), 2.30 (d, 1H), 2.66-2.80 (m, 2H), 2.84-3.10 (m, 3H), 3.34-3.43 (m, 1H), 5.51 (s, 1H), 6.97-7.05 (m, 2H), 7.19-7.28 (m, 2H). HRMS Calculated for [C16H19FN2O2+H]+: 291.1509. Found: 291.1497
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH2:6][C:7]3[C:12]([C:2]1=2)=[CH:11][CH:10]=[CH:9][CH:8]=3.C(C1SC=CC=1)=CC1C=CC=CC=1>>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[CH2:12][C:2]1=2
Reactant: c1ccc2c(c1)Cc1ccsc1-2
Agent: C(=Cc1cccs1)c1ccccc1
Product: c1ccc2c(c1)Cc1sccc1-2

Procedure:
The nitrogen in the above diazastilbenes and monoazastilbenes may be replaced with other heteroatoms and heterocycles to yield targets as shown in Scheme 71. ##STR91## For instance, 3-styrylthiophene (172) yields a photocyclization product (J. Chem. Soc. C, 2504 (1970) which may be converted by the methods described above to 4H-indeno[1,2-b]thiophene (173). Likewise, 2-styrylthiophene (175) is converted by photocyclization [J. Chem. Soc., 6221 (1965)] to an intermediate that will yield 8H-indeno[2,1-b]thiophene (176). These may then be alkylated by picolyl chloride to yield 4,4-bis(4-pyridinylmethyl)indeno[1,2-b]thiophene (174) and 8,8-bis(4-pyridinylmethyl)indeno[2,1-b]thiophene (177). Also, the furan derivatives are available via this route (Z. Naturfursch., Teil B, 24 (1969).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:5]2=[O:25].[H][H]>CO.[Pd]>[O:16]1[CH2:17][CH2:18][N:13]([CH2:12][C:7]2[O:8][C:9]3[C:4]([C:5](=[O:25])[C:6]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:3][CH:2]=[CH:11][CH:10]=3)[CH2:14][CH2:15]1
Reactant: [H][H]
Reactant: O=c1c(-c2ccccc2)c(CN2CCOCC2)oc2ccc(Br)cc12
Agent: [Pd]
Solvent: CO
Product: O=c1c(-c2ccccc2)c(CN2CCOCC2)oc2ccccc12
Yield: 100 %

Procedure:
To a solution of Example 2 (0.1 g, 0.249 mmoles) in methanol (10 ml), palladium on carbon 20 mg) was added and the solution was hydrogenated at RT under 5 kg/cm2 pressure of hydrogen for 4 h. The solution was filtered through celite and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as brown solid (0.080 g, 87% yield). 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 8.08(d, J=7.8Hz, 1H), 7.90(t, J=7.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.55(t, J=7.4 Hz, 1H), 7.49(m, 3H), 7.31(d, J=6.5 Hz, 2H), 3.72(br s,4H), 3.42(br s, 6H).
Reaction SMILES: [C:1]1([CH3:40])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([CH2:17][C:18](NC3C=CC(C4(CC(O)=O)CC5C(=CC=CC=5)C4)=CC=3)=[O:19])[CH:14]=[CH:13][C:11]=2[N:12]=1.C1(C)C(N=C=S)=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.C([OH:68])C>>[C:1]1([CH3:40])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([CH2:17][C:18]([OH:19])=[O:68])[CH:14]=[CH:13][C:11]=2[N:12]=1
Reactant: CCO
Reactant: Cc1ccccc1Nc1nc2ccc(CC(=O)Nc3ccc(C4(CC(=O)O)Cc5ccccc5C4)cc3)cc2o1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccccc1N=C=S
Product: Cc1ccccc1Nc1nc2ccc(CC(=O)O)cc2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (4-amino-3-hydroxy-phenyl)-acetic acid ethyl ester (3.3 g, Reference Example 3) and o-tolylisothiocyanate (2.5 mL) in ethanol (150 mL) was stirred at room temperature for about 2 hours. After standing at room temperature overnight the mixture was evaporated and the residue was subjected to flash chromatography on silica eluting with a mixture of pentane and ethyl acetate (7:3, v/v) to give a yellow foam. A solution of this material in ethanol (150 mL) was treated with dicyclohexylcarbodiimide (3.0 g) and the mixture was heated at reflux temperature for 2 hours. The mixture was evaporated and the residue subjected to short column chromatography (on silica eluting with a mixture of tert-butyl methyl ether and dichloromethane, 1:19 to 1:9 v/v). The resulting light yellow oil was dissolved in ethanol (100 mL) and the solution was treated with sodium hydroxide solution (15 mL, 1M) then heated at reflux temperature for 2 hours. The reaction mixture was evaporated and the residue was dissolved in water. The solution was washed with ethyl acetate and the aqueous layer was acidified to pH 1 by addition of concentrated hydrochloric acid. The resulting white precipitate was collected by filtration, then washed thoroughly with water, and then dried to give the title compound (1.8 g) as a white solid.
Reaction SMILES: [CH2:1]([N:8]([CH3:30])[C:9]1[C:17]2[S:16][C:15]([NH:18][C:19](=[O:27])[C:20]3[CH:25]=[CH:24][N:23]=[C:22](Br)[CH:21]=3)=[N:14][C:13]=2[C:12]([O:28][CH3:29])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:1]([N:8]([CH3:30])[C:9]1[C:17]2[S:16][C:15]([NH:18][C:19](=[O:27])[C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[CH:21]=3)=[N:14][C:13]=2[C:12]([O:28][CH3:29])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: COc1ccc(N(C)Cc2ccccc2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N(C)Cc2ccccc2)c2sc(NC(=O)c3ccnc(N4CCOCC4)c3)nc12

Procedure:
From N-[7-(benzyl-methyl-amino)-4-methoxy-benzothiazol-2-yl]-2-bromo-isonicotinamide with morpholine and cesium carbonate. ES-MS m/e (%): 490 (M+H+, 100).
Reaction SMILES: Cl.[NH2:2]N.C[N:5](C)/[CH:6]=[C:7](\[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)/[C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=1)=O>C(O)C>[CH3:17][S:16][C:12]1[N:11]=[C:10]([C:8]2[NH:2][N:5]=[CH:6][C:7]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=[CH:14][N:13]=1
Reactant: CSc1nccc(C(=O)/C(=C/N(C)C)c2ccccc2)n1
Reactant: NN
Agent: Cl
Solvent: CCO
Product: CSc1nccc(-c2[nH]ncc2-c2ccccc2)n1

Procedure:
Hydrazine hydrochloride (78 mg, 1.13 mmol, 1.5 equiv) was added to a solution of (2E)-3-(dimethylamino)-1-[2-(methylthio)pyrimidin-4-yl]-2-phenylprop-2-en-1-one(3-2, 226 mg, 0.76 mmol, 1 equiv) in ethanol (10 mL). The solution was refluxed for 3 hours and concentrated. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and concentrated to give 2-(methylthio)-4-(4-phenyl-1H-pyrazol-5-yl)pyrimidine (3-3) as a tan colored gum.