Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[C:6](=[O:16])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:4].[NH2:17][C@H:18]([C:20]([OH:22])=[O:21])[CH3:19].C[O-].[Na+]>COCCO>[OH:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[S:7][C:6](=[O:16])[C:5]=1[C:3]([NH:17][C@@H:18]([CH3:19])[C:20]([OH:22])=[O:21])=[O:4]
Reactant: C[C@H](N)C(=O)O
Reactant: COC(=O)c1c(O)c2ccccc2sc1=O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: C[C@H](NC(=O)c1c(O)c2ccccc2sc1=O)C(=O)O

Procedure:
A mixture of 4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester compound 3(c) (103 mg, 0.44 mmol), L-alanine (583 mg, 6.55 mmol) and NaOMe (285 mg, 5.28 mmol) in 2-methoxyethanol (14 mL) was refluxed for 6 h and concentrated. Residue was dissolved in water (100 mL) and acidified by 1 N HCl solution to pH=3-4. Precipitate was collected and rinsed with water. It was dried in vacuo and then triturated in MeOH (10 mL). Solid was collected and dried in vacuo to provide the title compound (57 mg). MS ESI(−) m/e: 291.12 (M−1).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15](=[NH:18])OC)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[ClH:19].[CH3:20][O:21][CH:22]([O:25][CH3:26])[CH2:23][NH2:24].C>CO>[ClH:19].[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:14][C:13]([C:15]([NH2:18])=[N:24][CH2:23][CH:22]([O:25][CH3:26])[O:21][CH3:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: COC(=N)c1ccc(-c2ccc(C(C)=O)cc2)o1
Reactant: COC(CN)OC
Agent: C
Agent: Cl
Solvent: CO
Product: COC(CN=C(N)c1ccc(-c2ccc(C(C)=O)cc2)o1)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
A mixture of 30 g (0.12 mole) of methyl 5-(4-acetylphenyl)-2-furimidate and 500 ml of saturated ethereal/HCl was stirred for 2 hrs. at room temperature and the resulting solid filtered. A mixture of this solid, 12.6 g (0.12 mole) of aminoacetaldehyde dimethyl acetal and 500 ml of methanol was refluxed for 3 hr. with the resulting solution being treated with Darco and filtered hot. The filtrate was taken to dryness on the Calab evaporator yielding a residual solid. This solid was dissolved in refluxing methanol (Darco), filtered and the filtrate cooled to room temperature. The filtrate was diluted with ether and the resulting solid filtered and air dried to yield 24 g (57%) of 5-(4-acetylphenyl)-N'-2,2-dimethoxyethyl-2-furamidine hydrochloride.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8].[OH:14][C:15]1[CH:41]=[CH:40][C:18]([CH2:19][O:20]/[N:21]=[C:22](/[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.CCCCCC.O>[O:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:5]1[O:6][C:7]([CH3:8])=[C:3]([CH2:2][O:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:19][O:20]/[N:21]=[C:22](/[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:40][CH:41]=2)[N:4]=1
Reactant: CCOC(=O)CCCCCC/C(=N\OCc1ccc(O)cc1)c1ccccc1
Reactant: Cc1oc(-c2ccco2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOC(=O)CCCCCC/C(=N\OCc1ccc(OCc2nc(-c3ccco3)oc2C)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.1 %

Procedure:
A mixture of 4-(chloromethyl)-2-(2-furyl)-5-methyloxazole (340 mg), ethyl E-8-(4-hydroxybenzyloxyimino)-8-phenyloctanoate (600 mg), potassium carbonate (432 mg) and N,N-dimethylformamide (7 ml) was stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain ethyl E-8-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyloxyimino]-8-phenyloctanoate (717 mg, yield 84%) as a colorless oil from an ethyl acetate-hexane (2:9, v/v)-eluted fraction.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1C=C(C)C=C(C)N=1.ClC(OC(C)(C)C(Cl)(Cl)Cl)=O.[NH2:41][C:42]1[CH:43]=[C:44]2[C:49](=[CH:50][CH:51]=1)[CH:48]=[N:47][CH:46]=[CH:45]2.C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C@H:10]([C:11]([NH:41][C:42]2[CH:43]=[C:44]3[C:49](=[CH:50][CH:51]=2)[CH:48]=[N:47][CH:46]=[CH:45]3)=[O:13])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)NC[C@@H](C(=O)O)c1ccc(Cl)cc1
Reactant: Nc1ccc2cnccc2c1
Agent: CC(C)(OC(=O)Cl)C(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: CC(C)(C)OC(=O)NC[C@@H](C(=O)Nc1ccc2cnccc2c1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To (S)-3-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)propanoic acid (28) (8.5 g, 28.4 mmol) in DMF cooled to 0° C. was added 2,4,6-trimethylpyridine and 2,2,2-trichloro-1,1-dimethylethyl chloroformate in DMF. Then, 6-aminoisoquinoline in DMF was added and the solution stirred for 2 h at 0° C. The mixture was poured into NaHCO3 (sat) and extracted with EtOAc. The organic layers were washed with H2O, dried (Na2SO4), filtered and evaporated to give crude 29. Column chromatography (30% EtOAc-Hexanes) and recrystallization (EtOAc/Hexanes) gave pure (S)-tert-butyl 2-(4-chlorophenyl)-3-(isoquinolin-6-ylamino)-3-oxopropylcarbamate (29, 7.8 g, 64%, >99% S enantiomer).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].N1C=CN=C1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C([O-])(O)=O.[Na+]>CN(C=O)C>[O:5]([CH2:1][CH2:2][C:3]#[CH:4])[Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#CCCO
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C#CCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.6 %

Procedure:
To a solution of 3-butyne-1-ol (21.0 g, 0.3 mol) in 100 mL of DMF was added imidazole (41.3 g, 0.6 mol), followed by a solution of t-butyldimethylsilyl chloride (48.0 g, 0.32 mol) in 25 mL of DMF. After stirring at room temperature under Ar for 18 h, the reaction mixture was poured into 10% aqueous NaHCO3 (150 mL) and extracted with hexane (3×250 mL). The organic phase was washed (brine), dried (Na2SO4) and evaporated to give 1-(t-butyl dimethylsiloxy)-3-butyne (49.0 g, 89%) as a colourless oil: IR (neat) 3320, 2125 (w) , 1260, 1110, 840 cm-1 ; 1H NMR (CDCl3, 200 MHz) δ3.74 (t, J=7.2 Hz, 2H), 2.40 (dt, J=7.1, 2.6 Hz, 2H), 1.96 (t, J=2.6 Hz, 1H), 0.90 (s, 9 H), 0.07 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[CH2:9][NH:8][CH2:7][CH2:6]2.I[CH:17]([CH2:19][CH3:20])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[CH2:9][N:8]([CH:17]([CH3:18])[CH2:19][CH3:20])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1[N+](=O)[O-])CNCC2
Reactant: CCC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCC(C)N1CCc2cc(OC)c([N+](=O)[O-])cc2C1
Temperature: 65 °C
Yield: 83.2 %

Procedure:
6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroisoquinoline (222 mg, 1.07 mmol) was dissolved in acetonitrile (5 mL), treated with 2-iodobutane (0.40 mL, 3.5 mmol) and potassium carbonate (500 mg, 3.62 mmol, Aldrich). The mixture was heated at 65° C. for 16 h, cooled, and partitioned between ethyl acetate and water. The organic layer was separated, dried over magnesium sulfate, filtered, concentrated, and purified by chromatography on SiO2 (0 to 20% methanol/dichloromethane spiked with aqueous ammonia) to provide 6-(methyloxy)-2-(1-methylpropyl)-7-nitro-1,2,3,4-tetrahydro isoquinoline (0.23 g, 0.89 mmol, 82%). 1H NMR (400 MHz, CDCl3) δ ppm 0.96 (t, J=7.2 Hz, 3 H), 1.06-1.18 (m, 3 H), 1.37-1.48 (m, 1 H), 1.63 (m, signal overlapped with H2O, 1 H), 2.64-3.08 (m, 5 H), 3.63-3.85 (m, 2 H), 3.93 (s, 3 H), 6.81 (s, 1 H), 7.63 (s, 1 H); ESIMS (M+H)+=265.
Reaction SMILES: [CH3:1][N:2]1[C@H:7]2[CH2:8][CH2:9][C@@H:3]1[CH2:4][CH:5]([C:10]#[N:11])[CH2:6]2>N.CO.[Ni]>[CH3:1][N:2]1[C@H:7]2[CH2:8][CH2:9][C@@H:3]1[CH2:4][CH:5]([CH2:10][NH2:11])[CH2:6]2
Reactant: CN1[C@@H]2CC[C@H]1CC(C#N)C2
Agent: [Ni]
Agent: N
Solvent: CO
Product: CN1[C@@H]2CC[C@H]1CC(CN)C2
Reaction time: 16 h
Yield: 37.7 %

Procedure:
To a solution of (1R,5S)-8-methyl-8-azabicyclo[3.2.1]octane-3-carbonitrile (J. Org. Chem., 1977, 3114) (83 mg, 0.55 mmol) in NH3/MeOH (0.5%) (10 mL) was added Raney Ni (ca. 50 mg). The reaction mixture was hydrogenated at atmospheric pressure for 16 hours. After filtration, the solvents were evaporated and the oil was purified by ion exchange on SCX-II acidic resin (2 g) eluting with methanol, then 2M ammonia-methanol. The basic fractions were combined and the solvent was removed in vacuo to give ((1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)methanamine as colourless oil (32 mg, 38%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH3:26])[NH:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].I[CH:28]([CH3:30])[CH3:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH3:26])[N:24]([CH:28]([CH3:30])[CH3:29])[CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CC(C)I
Reactant: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)c[nH]1
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cn1C(C)C

Procedure:
(S)—N-{1-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1-isopropyl-2-methyl-1H-imidazole-4-carboxamide was prepared using the method of Example 253 starting from (S)—N-{1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-2-methyl-1H-imidazole-4-carboxamide and 2-iodopropane. 1H NMR (400 MHz, CDCl3): 1.22 (3H, d), 1.43 (6H, d), 2.42 (3H, s), 4.29 (2H, m), 4.39 (1H, distorted dd), 4.57 (1H, m), 6.61 (1H, d), 7.49 (1H, d), 7.56 (1H, s), 7.59 (1H, d), 7.66 (1H, d), 7.86 (1H, dd), 8.00 (1H, d).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:12]2[N:13]=[C:14]3[CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17][CH2:16][N:15]3[C:11]=2[C:10]2[C:5](=[CH:6][C:7]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:8][CH:9]=2)[N:4]=1.C(OCC)C>ClCCl>[ClH:1].[ClH:1].[CH2:29]([O:28][C:7]1[CH:6]=[C:5]2[C:10]([C:11]3[N:15]4[CH2:16][CH2:17][CH2:18][NH:19][CH2:20][C:14]4=[N:13][C:12]=3[C:3]([NH2:2])=[N:4]2)=[CH:9][CH:8]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCCn2c(nc3c(N)nc4cc(OCc5ccccc5)ccc4c32)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Nc1nc2cc(OCc3ccccc3)ccc2c2c1nc1n2CCCNC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Hydrogen chloride (20 mL of 4 N in 1,4-dioxane) was added to a solution of tert-butyl 6-amino-3-benzyloxy-11,12-dihydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinolin-9(10H)-carboxylate (3.89 g, 8.46 mmol, prepared as described in Part A of Examples 435-450) in dichloromethane (50 mL), and the reaction was stirred at ambient temperature for one hour. Diethyl ether was added, and a precipitate formed. The precipitate was isolated by filtration and dried in a vacuum oven at 65° C. to provide 3.52 g of 3-benzyloxy-9,10,11,12-tetrahydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine dihydrochloride.
Reaction SMILES: [C:1]([C:4]1[CH:20]=[CH:19][CH:18]=[CH:17][C:5]=1[CH2:6][CH2:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15]#[N:16])[CH:11]=[CH:12][CH:13]=1)(O)=[O:2].[OH2:21]>>[O:2]=[C:1]1[C:13]2[CH:12]=[CH:11][C:10]([CH2:14][C:15]([NH2:16])=[O:21])=[CH:9][C:8]=2[CH2:7][CH2:6][C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]1=2
Reactant: O
Reactant: N#CCc1cccc(CCc2ccccc2C(=O)O)c1
Product: NC(=O)Cc1ccc2c(c1)CCc1ccccc1C2=O
Temperature: 100 °C

Procedure:
3-(2-Carboxyphenethyl)phenylacetonitrile (2 g.) is added to polyphosphoric acid (20 g.) [prepared from orthophosphoric acid (d = 1.7; 1,120 g.) and phosphorus pentoxide (1,300 g.)], and the mixture is heated for 2 hours at 100°C. After cooling, the reaction mixture is poured into water (250 cc.); the oil which separates out is extracted twice with methylene chloride (total 150 cc.). The combined organic extracts are washed and dried over anhydrous sodium sulphate (10 g.) and the solvent is evaporated under reduced pressure (20 mm.Hg) at 60°C. to give (5-oxo-10,11-dihydrodibenzo[a,d]cyclohepten-2-yl)acetamide (1.8 g.) melting at 174°C. After recrystallisation from ethanol, the product melts at 185°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[CH2:12]([NH:14][C:15]([C:17]1[C:21](Br)=[C:20]([C:23]2[CH:28]=[C:27]([Cl:29])[C:26]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:25][C:24]=2[O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:19][N:18]=1)=[O:16])[CH3:13].C(=O)([O-])O.[Na+].CN(C=O)C>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C.O>[CH2:12]([NH:14][C:15]([C:17]1[C:21]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[C:20]([C:23]2[CH:28]=[C:27]([Cl:29])[C:26]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:25][C:24]=2[O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:19][N:18]=1)=[O:16])[CH3:13]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1Br
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(OC)cc1
Temperature: 90 °C
Yield: 111.8 %

Procedure:
To a mixture of 4-methoxyphenylboronic acid (0.178 g, 1.17 mmol) and 5-(2,4-Bis-benzyloxy-5-chlorophenyl)-4-bromo-isoxazole-3-carboxylic acid ethylamide (0.507 g, 0.94 mmol) was added sodium hydrogen carbonate (237 mg, 2.82 mmol) followed by DMF (5 mL) and water (1.0 mL). The mixture was degassed by evacuation and flushing with nitrogen (three times), followed by bubbling nitrogen gas through mixture for five minutes. Dichlorobis(triphenylphosphine)palladium (II) (66 mg, 0.094 mmol) was added and reaction mixture was heated under a nitrogen atmosphere at 90° C. for two hours (reaction mixture becomes dark brown in colour). Another 10 mg of dichlorobis(triphenylphosphine)palladium (II) was added and reaction mixture was heated at 90° C. for 15 hours then allowed to cool to ambient temperature. The majority of solvents were removed in vacuo and the residue was partitioned between ethyl acetate (50 mL) and water (50 mL). This mixture was filtered through a pad of celite to remove palladium residues and then the phases were separated and the organic phase was washed with water (2×30 mL), saturated aqueous sodium chloride solution (50 mL) then dried over sodium sulphate. The mixture was filtered and the filtrate solvents were removed in vacuo to afford a yellow oil (598 mg). The crude reaction product was purified by adsorption onto silica gel then flash chromatography on silica gel (20 g IST) eluting with a solvent gradient of 1 to 20% ethyl acetate in hexane. This affords 5-(2,4-Bis-benzyloxy-5-chlorophenyl)-4-(4-methoxy-phenyl)-isoxazole-3-carboxylic acid ethylamide as a colourless solid (0.223 g, 40%). LCMS: [M+H]+ 571, 569 (37Cl; 35Cl). 1H NMR (400 MHz, CDCl3) δ 1.21 (t, 3H), 3.44 (m, 2H), 3.79 (s, 3H), 4.73 (s, 2H), 6.45 (s, 1H), 6.65 (t, 1H), 6.80 (d, 2H), 7.14 to 7.44 (m, 8H), 6.95 (m 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([N:12]1[CH2:17][CH2:16][O:15][C@H:14]([CH3:18])[CH2:13]1)=[CH:8][C:7]2=[O:19].[C:24]([O:28][C:29]([N:31]1[CH:35]=[CH:34][CH:33]=[C:32]1B(O)O)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:23][O:22][C:20]([C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([C:32]3[N:31]([C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH:35]=[CH:34][CH:33]=3)[CH:3]=1)[O:10][C:9]([N:12]1[CH2:17][CH2:16][O:15][C@H:14]([CH3:18])[CH2:13]1)=[CH:8][C:7]2=[O:19])=[O:21]
Reactant: COC(=O)c1cc(Br)c2oc(N3CCO[C@H](C)C3)cc(=O)c2c1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(-c2cccn2C(=O)OC(C)(C)C)c2oc(N3CCO[C@H](C)C3)cc(=O)c2c1
Temperature: 80 °C
Yield: 20 %

Procedure:
Bis(triphenylphosphine) palladium(II) chloride (0.448 g, 0.63 mmol) was added in one portion to a stirred slurry of (R)-methyl 8-bromo-2-(2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylate (10.06 g, 25 mmol), 1-(tert-butoxycarbonyl)-1H-pyrrol-2-ylboronic acid (6.46 g, 30.00 mmol) and sodium carbonate (7.95 g, 75.00 mmol) in DME (140 mL) and water (28 mL). The mixture was degassed with argon for 15 mins then heated at 80° C. for 6 h. The solvent was evaporated, water was added to the residue and the mixture was extracted with DCM. The combined organic phases were washed with water, brine, dried over MgSO4 and concentrated to give crude (R)-tert-butyl 2-(6-(methoxycarbonyl)-2-(2-methylmorpholino)-4-oxo-4H-chromen-8-yl)-1H-pyrrole-1-carboxylate containing ˜20% of starting material (13.98 g). Mass Spectrum: m/z [M+H]+=469.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[C:9]1[NH:14][C:13](=[O:15])[C:12]([C:16]#N)=[CH:11][C:10]=1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1.C[Si](C)(C)N[Si](C)(C)C.[H-].C([Al+]CC(C)C)C(C)C.CC[O:46]C(C)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[NH:14][C:13](=[O:15])[C:12]([CH:16]=[O:46])=[CH:11][C:10]=1[C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)[nH]c1=O
Reactant: CCOC(C)=O
Agent: CC(C)C[Al+]CC(C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)[nH]c1=O

Procedure:
An oven dried three-necked 250 mL 14/20 standard taper round bottom flask was equipped with a magnetic stir bar and a rubber septum, a glass stopper, and a reflux condenser in each of the three necks. A piece of vacuum tubing from a Firestone valve was connected to a tubing adapter placed at the top of the condenser. The flask was then charged with a suspension of 10.473 g (30.7 mmol) of 6-(2-chlorophenyl)-5-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (prepared in similar fashion to Step B Example 1) in 35 mL toluene, the atmosphere in the reaction vessel was replaced with nitrogen by cycling the Firestone valve, and finally hexamethyldisilazane (6.40 mL, 30.7 mmol) was added via syringe. The reaction mixture was stirred and gently refluxed for 2.5 h, then cooled and stirred at −40° C. using an external dry ice-acetone bath and diisobutylaluminum hydride (31.0 mL, 46.0 mmol) was then slowly added by syringe. The reaction mixture was stirred at −40° to −30° C. for 3 h at which point LC/MS analysis of an acid-quenched aliquot indicated that the reduction was complete. The cooling bath was removed and the reaction was quenched by dropwise addition of 40 mL of 2 N HCl. After gas evolution had ceased, the reaction mixture was transferred to a 1 L Erlenmeyer flask using 100 mL THF to rinse the solids. Additional 2 N HCl was added (200 mL), and the two phase mixture was stirred and heated for 30 min on a hot plate to ensure complete hydrolysis of the intermediate imine. EtOAc (200 mL) was added and the reaction mixture was stirred and heated until the solids had dissolved. The organic layer was separated, evaporated to dryness, then redissolved in EtOAc. The aq layer was adjusted to pH=7 with 6 N sodium hydroxide solution, then added back to organic layer. The layers were again heated and magnetically stirred to dissolve all the solids, then separated. The aq layer was washed with additional hot EtOAc, the organic layers were combined and then washed with water, brine, then dried (MgSO4), filtered and slowly evaporated. The product was crystallized from the EtOAc solution during the evaporation process and collected by vacuum filtration. The yellow crystalline solid was dried in vacuo to afford the title compound. HPLC/MS: 344.1 (M+1), 346.1 (M+3); Rt=3.17 min.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:9][C:10]#[CH:11]>>[C:12]1([CH2:8][CH2:9][C:10]#[C:11][C:2]2[N:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C#CCCc1ccccc1
Reactant: Brc1ncccn1
Product: C(#Cc1ncccn1)CCc1ccccc1
Yield: 85.7 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyrimidine (290 mg, 1.82 mmol) and 1-(but-3-ynyl)benzene (200 mg, 1.54 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 85:15) to yield 275 mg (1.32 mmol, 86%) of 2-(4-phenylbut-1-ynyl)pyrimidine as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([N:13]2[C:29]3[C:16](=[CH:17][C:18]4[O:19][CH2:20][C:21]5[N:26]([C:27]=4[CH:28]=3)[C@H:25]([CH3:30])[C:24](=[O:31])[NH:23][N:22]=5)[C:15](I)=[CH:14]2)([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:33][C:34]1(C)C(C)(C)OB(C=C)O1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>O1CCOCC1.O.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.Cl[Pd]Cl.[Fe+2]>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([CH3:12])([N:13]2[C:29]3[C:16](=[CH:17][C:18]4[O:19][CH2:20][C:21]5[N:26]([C:27]=4[CH:28]=3)[C@H:25]([CH3:30])[C:24](=[O:31])[NH:23][N:22]=5)[C:15]([CH:33]=[CH2:34])=[CH:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1C(=O)NN=C2COc3cc4c(I)cn(C5(C)CN(C(=O)OC(C)(C)C)C5)c4cc3N21
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: C=Cc1cn(C2(C)CN(C(=O)OC(C)(C)C)C2)c2cc3c(cc12)OCC1=NNC(=O)[C@@H](C)N13
Temperature: 25 °C
Yield: 89.6 %

Procedure:
A mixture of 3-((R)-8-iodo-1-methyl-2-oxo-1,2,3,5-tetrahydro-6-oxa-3,4,10,11b-tetraaza-cyclopenta[b]phenanthren-10-yl)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.3 g, 0.544 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.838 g, 5.44 mmol), K2CO3 (0.15 g, 1.088 mmol) and Pd(dppf)Cl2.CH2Cl2 (0.044 g, 0.054 mmol) in dioxane (6 mL) and water (1 mL) was heated at 68° C. for 14 h. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (eluting with 10%˜100% EtOAc in petroleum ether) to give 3-methyl-3-((R)-1-methyl-2-oxo-8-vinyl-1,2,3,5-tetrahydro-6-oxa-3,4,10,11b-tetraaza-cyclopenta[b]phenanthren-10-yl)-azetidine-1-carboxylic acid tert-butyl ester (0.22 g, 90%) as yellow gum, which was used directly in the next step. LC/MS (Table 1, Method 25) Rt=0.892 min.; MS m/z: 452 [M+H]+.