Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[C:22]3[C:17](=[CH:18][C:19]([C:23]#[N:24])=[CH:20][CH:21]=3)[N:16](CC)[CH:15]=2)=[C:9]([Br:27])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C[NH-].C(C1C=C2C(C=CN2)=CC=1)#N.CC(C)([O-:45])C.[K+]>C(O)(C)(C)C.C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([C:23]#[N:24])=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[OH:45])=[C:9]([Br:27])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[O-]
Reactant: CCn1cc(Cc2ccc(C(=O)OC(C)(C)C)cc2Br)c2ccc(C#N)cc21
Agent: C[NH-]
Agent: N#Cc1ccc2cc[nH]c2c1
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(C(O)c2c[nH]c3cc(C#N)ccc23)c(Br)c1
Temperature: 25 °C
Yield: 79 %

Procedure:
Part A. 3-bromo-4-(6-cyano-1-ethyl-1H-indol-3-ylmethyl)-benzoic acid tert-butyl ester: A mixture of the compound of Example 10, Part A (5 g, 0.175 mol) and 6-cyanoindole (1.7 g, 0.0.12 mol) in t-butanol (60 ml) and THF (˜5 mL) was treated with potassium t-butoxide (0.012 mol) and the mixture was stirred at rt under N2. After 18 h the reaction mixture was diluted with EtOAc and washed with water and brine, dried over anh. Na2SO4, filtered and solvent evaporated. The residue was purified by flash chromatography on silica gel to provide 3-Bromo-4-[(6-cyano-1H-indol-3-yl)-hydroxy-methyl]-benzoic acid tert-butyl ester (4.05 g, 79%) as an off-white foam. 1H NMR (400 MHz, CDCl3) δ ppm 1.58 (s, 9H) 2.43 (d, J=0.39 Hz, 1H) 6.47 (d, J=0.39 Hz, 1H) 7.11 (d, J=2.20 Hz, 1H) 7.36 (d, J=8.35 Hz, 1H) 7.70 (s, 1H) 7.78 (dd, J=15.60, 8.13 Hz, 2H) 7.98 (m, 1H) 8.14 (s, 1H) 8.39 (s, 1H). This material was dissolved in methylene chloride (55 ml) and cooled in an ice/salt water bath under N2. To the cold, stirred solution was added triethylsilane (3.03 mL, 2 eq) followed by slow addition of trifluoroacetic acid (0.72 mL, 1 eq) over 20-25 min. The resulting solution was stirred for 1 h allowing ice bath to melt and reaction to gradually assume rt. Additional methylene chloride was added and the solution was washed with brine, dried and evaporated.
Reaction SMILES: [F:1][C:2]1[S:3][C:4]2[CH2:9][CH2:8][CH:7]([C:10]([O:12]CC)=[O:11])[C:5]=2[N:6]=1.[OH-].[Li+].Cl>C1COCC1.CO>[F:1][C:2]1[S:3][C:4]2[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=[O:11])[C:5]=2[N:6]=1
Reactant: CCOC(=O)C1CCc2sc(F)nc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1CCc2sc(F)nc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the product from step A (100 mg, 0.456 mmol) in a mixture of THF (1.5 mL) and methanol (0.5 mL) was added a solution of lithium hydroxide (0.558 mL of a 1 M soln, 0.588 mmol) and the resulting mixture stirred at room temperature for 90 mins. 1N HCl (0.558 mL, 0.558 mmol) was added and the mixture evaporated to dryness. The resulting crude product was used immediately without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]2[CH2:19][CH2:18][C:17]3[NH:16][C:15](=[O:20])[CH:14]([CH3:21])[CH2:13][C:12]=3[CH2:11]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C([SiH](CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH:10]2[CH2:19][CH2:18][CH:17]3[CH:12]([CH2:13][CH:14]([CH3:21])[C:15](=[O:20])[NH:16]3)[CH2:11]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(CC2CCC3=C(C2)CC(C)C(=O)N3)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CC2CCC3NC(=O)C(C)CC3C2)cc1
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
3,4,5,6,7,8-Hexahydro-6-((4-methoxyphenyl)methyl)-3-methylquinolin-2[1H]-one (0.25 g) prepared according to Example 1, was suspended in triethylsilane (0.5 ml) and trifluoroacetic acid (0.5 ml) was added. The mixture was stirred for 30 minutes and then evaporated under reduced pressure. The residue was dissolved in chloroform and washed with saturated sodium carbonate solution and then with brine. The organic solution was dried (MgSO4) and evaporated to give the crude product (0.28 g), which was combined with a further batch 0.38 g. The crude product was purified by crystallisation from ethyl acetate/cyclohexane to give the title compound (0.2 g) m.p. 180°-208° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:6](=[O:7])[NH:5][C:3]1=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][CH:17]([O:21][CH3:22])[CH2:18][CH2:19]Br>CS(C)=O>[CH3:15][O:16][CH:17]([O:21][CH3:22])[CH2:18][CH2:19][N:5]1[C:6](=[O:7])[CH2:8][N:2]([CH3:1])[C:3]1=[O:4]
Reactant: COC(CCBr)OC
Reactant: CN1CC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(CCN1C(=O)CN(C)C1=O)OC
Temperature: 5 °C

Procedure:
13.24 g (116 mmol) 1-methylhydantoin, 19.34 g (140 mmol) waterfree potassium carbonate and 29.2 g (3-bromo-propionaldehyd-dimethylacetal are allowed to react in 90 ml dimethylsulfoxid for 3 hours and 25 minutes at 112°-115° C. The reaction mixture is subsequently cooled to 5° C. and filtered with suction. The filtrate is evaporated in a rotary evaporator and the liquid crude product is purified by fractional distillation in vacuo to give 12.44 g (49.6% of theory) liquid 3-(3,3-dimethoxy-propyl)-1-methyl-imidazolidin-2,4-dione, having a boiling point of 112°-114° C./0.07 mbar.
Reaction SMILES: Br[C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=[CH2:15].C(N(C(C)C)CC)(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:18]([O:17][C:13](=[O:16])[C:14]([C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1)=[CH2:15])[CH3:19]
Reactant: C=CC(=O)OCC
Reactant: Brc1cnc2c(c1)OCCCN2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: C=C(C(=O)OCC)c1cnc2c(c1)OCCCN2
Temperature: 100 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
A solution of 3-bromo-6,7,8,9-tetrahydro-5-oxa-1,9-diaza-benzocycloheptene (1.1 g, 4.80 mmol), ethyl acrylate (1.5 mL, 14.4 mmol) and diisopropylethylamine (2.5 mL, 14.4 mmol) in propionitrile (100 mL) was purged with an Argon stream for 10 min. Pd(OAc)2 (108 mg, 048 mmol) and P(o-Tol)3 (292 g, 0.96 mmol) were added and the Argon purge was repeated. The mixture was stirred at 100° C. for 8 h under Argon. Upon cooling, the resultant mixture was filtered through celite; the filtrate was evaporated. The crude product was purified by chromatography (silica, 0-2% MeOH in CH2Cl2) to afford the title compound (0.753 g, 63%). 1H NMR (300 MHz, DMSO-d6, 6): 7.98 (d, J=1.9 Hz, 1H), 7.52 (d, J=1.9 Hz, 1H), 7.51 (d, J=16 Hz, 1H), 6.83 (s, br, 1H), 6.42 (d, J=16 Hz, 1H), 4.15 (m, 4H), 3.34 (m, 2H), 1.98 (m, 2H), 1.25 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]1[C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][NH:2]1.[N:10]([O-])=[O:11].[Na+]>Cl.O>[N:10]([CH:1]1[C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][NH:2]1)=[O:11]
Reactant: O=N[O-]
Reactant: C1CC[C@H]2CNC[C@H]2C1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=NC1NC[C@@H]2CCCC[C@H]12
Yield: 54.6 %

Procedure:
cis-Octahydro-1H-isoindole (1.81 g, 14.5 mmol), which is the compound described in Tetrahedron, 55 (1999) 9439-9454, was dissolved in 1N hydrochloric acid (16 ml), and the mixture was stirred under ice-cooling, sodium nitrite (6.22 g, 90.1 mmol) dissolved in water (20 ml) was gradually added, and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was extracted with diethyl ether, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. Me insoluble material was filtered off, and the solution was concentrated under reduced pressure to give the title compound (1.22 g, yield 55%) as a bistered oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:14](OC)(=[O:19])[C:15]([O:17][CH3:18])=[O:16].[Li+].CC([N-]C(C)C)C>C1COCC1>[CH2:6]([O:5][CH:4]([C:14](=[O:19])[C:15]([O:17][CH3:18])=[O:16])[C:3]([O:2][CH3:1])=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)COCc1ccccc1
Reactant: COC(=O)C(=O)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(=O)C(OCc1ccccc1)C(=O)OC

Procedure:
A solution of methyl(benzyloxy)acetate (1 eq) and dimethyl oxalate (1.2 eq) in dry THF was cooled to −78° C. and LDA (2M in THF-heptane, 1.2 eq) was added dropwise. After stirring for an hour the cold bath was removed, and stirring was continued for an additional hour. The reaction was quenched at 0° C. by pouring into cold 1N aq HCl, and the aqueous phase was extracted with EtOAc; the organic layer was washed with brine, dried and concentrated to give a crude that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C@H:14]3[C:18]([CH3:20])([CH3:19])[C@:11]([CH3:21])([CH2:12][CH2:13]3)[C:10]=2[NH:9]1.I[CH2:23][CH3:24]>CN1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C@H:14]3[C:18]([CH3:20])([CH3:19])[C@:11]([CH3:21])([CH2:12][CH2:13]3)[C:10]=2[N:9]1[CH2:23][CH3:24]
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccccc3Cl)c(=O)c12
Reactant: CCI
Agent: CN1CCCC1
Solvent: CCOC(C)=O
Product: CCn1c2c(c(=O)n1-c1ccccc1Cl)[C@@H]1CC[C@@]2(C)C1(C)C
Yield: 45.9 %

Procedure:
A solution of (4R,7S)-2-(2-chloro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 39; 151 mg, 0.5 mmol) and iodoethane (0.21 mL, 2.58 mmol) in N-methylpyrrolidine (1 mL) was heated at 100° C. in a sealed tube overnight. The reaction mixture was purified by preparative HPLC to give a brown gum which was dissolved in ethyl acetate. The solution was washed with 10% aqueous sodium thiosulfate (three times) and brine, dried (sodium sulfate), filtered, evaporated, and dried under high vacuum to give (4R,7S)-2-(2-chloro-phenyl)-1-ethyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (76 mg, 46%) as an off-white foam. ES(+)-MS (M+H) 331.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[C:9]([C:26]#[N:27])=[N:8]2)=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:38]5[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[C:9]([C:26]#[N:27])=[N:8]2)=[C:4]([C:30]([F:32])([F:33])[F:31])[CH:3]=1
Reactant: CN1CCNCC1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(c2)c(C#N)nn3Cc2ccc(Cl)cc2C(F)(F)F)S1
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(c3)c(C#N)nn4Cc3ccc(Cl)cc3C(F)(F)F)S2)CC1

Procedure:
1-[4-Chloro-2-(trifluoromethyl)benzyl]-5-{[2-(4-methylpiperazin-1-yl)-4-oxo-1,3-thiazol-5(4H)-ylidene]methyl}-1H-indazole-3-carbonitrile was prepared from 1-(4-Chloro-2-trifluoromethyl-benzyl)-5-(2-ethylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-1H-indazole-3-carbonitrile and 1-Methyl-piperazine following General Procedure C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:5]2.C(N(CC)CC)C.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:1]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:5]2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cnc2ccc(O)cc2c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc2ccc(Oc3ccccc3)cc2c1
Temperature: 25 °C

Procedure:
To a mixture of methyl 6-hydroxyquinoline-3-carboxylate (0.142 g, 0.699 mmol) in methylene chloride (7 mL) and triethylamine (0.974 mL, 6.99 mmol) were added phenylboronic acid (197 mg, 1.62 mmol), copper(II) acetate (294 mg, 1.62 mmol) and 4 Å molecular sieves (approx 200 mg). The mixture was stirred at room temperature over night. Solids were removed from the reaction mixture by filtration and the filter pad was washed thoroughly with ethyl acetate. The filtrate was washed twice with ammonium hydroxide solution and then brine. The extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (hexanes to 50/50 hexanes/ethyl acetate gradient) to afford Int-17 (0.143 g, 73%). LC-MS: (FA) ES+280; 1H NMR (400 MHz, d6-DMSO) δ ppm 9.22 (d, J=2.1 Hz, 1H), 8.95 (d, J=1.8 Hz, 1H), 8.13 (d, J=8.8 Hz, 1H), 7.70-7.66 (m, 2H), 7.49-7.43 (m, 2H), 7.23 (tt, J=7.5, 7.5, 1.1, 1.1 Hz, 1H), 7.17-7.13 (m, 2H), 3.93 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][C:10]2([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11]2)[CH:3]=1.[F:20][C:21]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[NH2:8][C:6]1[N:7]=[C:2]([C:27]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([F:20])[CH:28]=2)[CH:3]=[C:4]([NH:9][C:10]2([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11]2)[N:5]=1
Reactant: Nc1nc(Cl)cc(NC2(Cc3ccccc3)CC2)n1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cc(NC3(Cc4ccccc4)CC3)nc(N)n2)cc1F
Temperature: 110 °C
Yield: 51.5 %

Procedure:
A mixture of 6-chloro-N4-[1-(phenylmethyl)cyclopropyl]-2,4-pyrimidinediamine (185 mg, 0.67 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (247 mg, 1 mmol), Pd(PPh3)4 (81 mg, 0.07 mmol) and Na2CO3 (178 mg, 1.68 mmol) in 1,4-dioxane (30 mL) and water (10 mL) was stirred and heated at 110° C. for 3.5 hours under nitrogen. Then the mixture was cooled to room temperature and concentrated. The resulting residue was portioned between EtOAc and water. The aqueous was extracted with EtOAc (2×50 mL), and the organics were dried (MgSO4), filtered, concentrated to dryness, and purified by SGC using a petroleum ether to 4:1 petroleum ether/EtOAc to 1:1 petroleum ether/EtOAc as eluent to afford the title compound (124 mg) as a brown oil solid. LC-MS (ES) m/z=360 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:19]=[CH:18][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br>C(O)(=O)C>[CH3:1][S:2]([C:5]1[CH:19]=[CH:18][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: COc1ccc(Oc2ccc(S(C)(=O)=O)cc2)cc1
Agent: Br
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(Oc2ccc(O)cc2)cc1
Yield: 98.8 %

Procedure:
A solution of 37.3 g of 4-(4-(methylsulfonyl)phenoxy)-1-methoxybenzene (Example 18), 41 ml of 48% aqueous hydrogen bromide and 185 ml of glacial acetic acid was heated at reflux under nitrogen for 21 hrs. The reaction mixture was cooled and the solvent removed in vacuo. The product was collected by filtration, washed well with water and dried, which gave 35.0 g (98.9% yield) of the product. Recrystallization from aqueous ethanol gave purified 4-(4-(methylsulfonyl)phenoxy)phenol, mp 129°-130° C.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([CH:12]3[CH2:17][CH2:16][N:15](C(=O)C)[CH2:14][CH2:13]3)=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O>[C:1]1([C:7]2[O:11][C:10]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[N:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)N1CCC(c2ncc(-c3ccccc3)o2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: c1ccc(-c2cnc(C3CCNCC3)o2)cc1
Temperature: 75 °C

Procedure:
A solution of 1-[4-(5-phenyl-oxazol-2-yl)-piperidin-1-yl]-ethanone (30.0 g, 110.99 mmol), prepared as part B, in MeOH (450 ml) is treated with a solution of NaOH (44.40 g, 1109.90 mmol) in water (150 ml), heated at 75° C. for 18 hours, and then the reaction mixture is concentrated to 1/3 volume. Upon addition of ca. an equal volume of water, crystallization occurred. The solids are filtered, washed with water and dried in a vacuum over at 70° C. to afford 4-(5-phenyl-oxazol-2yl)-piperidine as a white solid. 1HNMR (CDCl3): d 7.61 (d, 2H, J=7.4 Hz), 7.40 (t, 2H, J=7.4 Hz), 7.30 (t, 1H, J=7.4 Hz), 7.23 (s, 1H), 3.19 (d t, 2H, J=11.8, 3.3 hz), 2.99 (t t, 1H, J=11.8 3.9 Hz), 2.76 (m, 2H), 2.10 (m, 2H), 1.82 (m, 2H).
Reaction SMILES: Cl.CN([CH2:5][C:6]1[C:7](=[O:13])[NH:8][C:9](=[O:12])[NH:10][CH:11]=1)C.[CH3:14][O:15][C:16]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:17]=1[NH2:18].COC1C=CC=C(OC)C=1C(O)=O>C(O)CO>[NH2:18][C:17]1[C:19]([O:23][CH3:24])=[CH:20][C:21]([CH2:5][C:6]2[C:7](=[O:13])[NH:8][C:9](=[O:12])[NH:10][CH:11]=2)=[CH:22][C:16]=1[O:15][CH3:14]
Reactant: CN(C)Cc1c[nH]c(=O)[nH]c1=O
Reactant: COc1cccc(OC)c1N
Agent: COc1cccc(OC)c1C(=O)O
Agent: Cl
Solvent: OCCO
Product: COc1cc(Cc2c[nH]c(=O)[nH]c2=O)cc(OC)c1N
Yield: 28.8 %

Procedure:
A mixture of 10.04 g (49 mmol) of 5-[(dimethylamino)methyl]uracil hydrochloride (B. Roth, J. Z. Strelitz, and B. S. Rauckman, J. Med. Chem. 23, 379 (1980) and 7.48 g (49 mmol) of 2,6-dimethoxyaniline (m.p. 73°-74.5°; prepared from 2,6-dimethoxybenzoic acid by the procedure in Org. Reactions 3, 330 (1946)) in 50 mL of ethylene glycol under nitrogen was heated at 145° for 5 hours. The mixture was cooled and the precipitated solid was collected, suspended in 300 mL of boiling ethanol and collected to give 3.91 g (29%) of the title compound; m.p. 243°-245° (dec.).
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[P:9]([O-:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12].C1(C)C=CC=CC=1>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.O>[N:6]1[CH:7]=[CH:8][C:3]([P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[CH:4][CH:5]=1
Reactant: Brc1ccncc1
Reactant: CCOP([O-])OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CCOP(=O)(OCC)c1ccncc1

Procedure:
4-Bromopyridine hydrochloride (8 g, 41.1 mmol), diethyl phosphite (8.23 mL, 63.8 mmol), tetrakis(triphenylphosphine)palladium(0) (1.189 g, 1.029 mmol) and TEA (17.20 mL, 123 mmol) were stirred in refluxing toluene (160 mL) overnight. Room temperature was attained, water was added and the organic layer separated. The aqueous phase was extracted with EtOAc (×2). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by MPLC (EtOAc) gave diethyl pyridin-4-ylphosphonate as a pale yellow oil. 1H NMR (DMSO-d6, 600 MHz) δ 8.75 (m, 2H), 7.61 (m, 2H), 4.03 (m, 4H), 1.21 (t, J=7.2 Hz, 6H). MS: cal'd 216 (MH+), exp 216 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13](=O)/[CH:14]=[C:15](\[O-])/[C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].Cl.Cl.[NH2:26][NH2:27]>C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:27][N:26]=2)[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C([O-])=C/C(=O)c1cn(Cc2ccccc2)cn1
Reactant: NN
Agent: Cl
Agent: [Li+]
Solvent: CCO
Product: CCOC(=O)c1cc(-c2cn(Cc3ccccc3)cn2)n[nH]1
Temperature: 25 °C
Yield: 90 %

Procedure:
Lithium (Z)-4-(1-benzyl-1H-imidazol-4-yl)-1-ethoxy-1,4-dioxobut-2-en-2-olate (9.80 mmol, 3.0 g) was suspended in dry ethanol (20 ml). Hydrazine dihydro-chloride (12.74 mmol, 1.337 g) was added and the resulting mixture was refluxed for 2 h. The mixture was cooled to ambient temperature and evaporated. The sticky oil was purified by trituration from ethanol. The precipitate was separated by filtration and flushed with cold ethanol. 2.614 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.31 (t, 3H), 4.33 (q, 2H), 5.81 (bs, 2H), 7.11-7.39 (m, 6H), 8.16 (bs, 1H), 9.31 (bs, 1H), 14.50 (bs, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH:7]=[C:6]([C:19]#[N:20])[C:5]2=[O:21].[CH3:22][NH:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:18][C:15]1[CH:16]=[CH:17][C:12]([N:8]2[C:9]3[C:4](=[CH:3][C:2]([N:23]([CH3:22])[CH2:24][C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)=[CH:11][CH:10]=3)[C:5](=[O:21])[C:6]([C:19]#[N:20])=[CH:7]2)=[CH:13][CH:14]=1
Reactant: N#Cc1cn(-c2ccc(F)cc2)c2ccc(Br)cc2c1=O
Reactant: CNCc1cccnc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CN(Cc1cccnc1)c1ccc2c(c1)c(=O)c(C#N)cn2-c1ccc(F)cc1
Temperature: 110 °C
Yield: 40.3 %

Procedure:
Compound W (25 mg, 0.073 mmol, 1.0 eq), N-methyl-N-(3-pyridylmethyl)amine (17 mg, 0.15 mmol, 2.0 eq), cesium carbonate (33 mg, 0.10 mmol, 1.4 eq), tris(dibenzylideneacetone)dipalladium(0) (5.3 mg, 0.0058 mmol, 0.080 eq) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (5.1 mg, 0.0087 mmol, 0.12 eq) were dissolved in toluene (0.5 mL) in a sealed vial and heated at 110° C. overnight. The reaction was cooled, filtered over Celite® and washed with 5% methanol in DCM. The organics were concentrated and purified using reverse phase chromatography to afford 11.3 mg (40%) of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.44-8.42 (m, 2H), 7.70-7.67 (m, 2H), 7.57 (dt, J=7.8, 1.8 Hz, 1H), 7.48 (t, J=8.7 Hz, 2H), 7.33-7.32 (m, 2H), 7.26 (dd, J=9.4, 3.1 Hz, 1H), 6.83 (d, J=9.3 Hz, 1H), 4.72 (s, 2H), 3.1 (s, 3H); ES-MS [M+1]+: 385.2.
Reaction SMILES: [CH3:1][NH2:2].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[C:4]1[C:12](Cl)=[O:13]>C1COCC1>[CH3:1][NH:2][C:12]([C:4]1[S:3][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=1)=[O:13]
Reactant: CN
Reactant: O=C(Cl)c1cc2ccccc2s1
Solvent: C1CCOC1
Product: CNC(=O)c1cc2ccccc2s1
Temperature: 25 °C
Yield: 98 %

Procedure:
To a stirred solution of 2.0 M methylamine in THF (60 mL) and THF (60 mL) was added dropwise at 0° C. a solution of benzothiophene-2-carbonyl chloride (10.8 g, 55 mmole) in THF (50 mL) over 15 minutes. After the addition-the reaction was allowed to warm to RT then was concentrated under vacuum. Trituration with a cold solution of 4:1 H2O/methanol (50 mL), filtration, and drying under vacuum gave the title compound (10.35 g, 98%) as a white solid: MS (ES) m/e 191.9 (M+H)+.
Reaction SMILES: Cl.[C:2]1([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]3[O:24][CH2:23][CH2:22][C@@H:21]4[C@H:16]([O:17][CH2:18][CH2:19][NH:20]4)[C:14]=3[CH:15]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)Cl>[C:32]([N:20]1[CH2:19][CH2:18][O:17][C@@H:16]2[C:14]3[CH:15]=[C:10]([O:9][CH2:8][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:11]=[CH:12][C:13]=3[O:24][CH2:23][CH2:22][C@@H:21]12)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: c1ccc(COc2ccc3c(c2)[C@H]2OCCN[C@@H]2CCO3)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCO[C@@H]2c3cc(OCc4ccccc4)ccc3OCC[C@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3.47 g of trans-10-phenylmethoxy-3,4,4a,5,6,11b-hexahydro-2H-[1]benzoxepino[5,4-b]-1,4-oxazine hydrochloride, 50 ml of triethylamine and 25 ml of methylene chloride is cooled in ice and 1.0 ml of acetyl chloride dissolved in 25 ml of methylene chloride is added dropwise thereto. The solution is stirred overnight at room temperature, washed with a dilute hydrochloric acid solution and dried over anhydrous magnesium sulfate. The drying agent is removed via filtration and the filtrate evaporated to yield trans-4-acetyl-10-phenylmethoxy-3,4,4a,5,6,11b-hexahydro-2H-[1]benzoxepino[5,4-b]-1,4-oxazine as an oil.