Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].BrC[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([CH2:17][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccc([N+](=O)[O-])cc3)CC1)O2
Yield: 93.2 %

Procedure:
(E)-3-{4-Oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (337 mg, 1.00 mmol, Intermediate 1, hydrochloride salt) was alkylated using 1-(2-bromo-ethyl)-4-nitro-benzene (460 mg, 2 mmol) as described in Example 56, Step A, giving (E)-3-{1′-[2-(4-nitro-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (420 mg) as a light brown solid.
Reaction SMILES: O=[C:2]1[CH2:11][N:10]2[C@H:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][C@H:13]3[C:8]3[C:9]2=C([CH:5]=[CH:6][CH:7]=3)N1.[H-].[Na+].CI.[CH3:27][N:28]([CH:30]=[O:31])[CH3:29]>O>[CH3:2][CH:11]1[N:10]2[C:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][C:13]=3[C:8]3[C:9]2=[C:27]([CH:5]=[CH:6][CH:7]=3)[N:28]([CH3:29])[C:30]1=[O:31]
Reactant: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CC(=O)N3
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CCOC(=O)N1CCc2c(c3cccc4c3n2C(C)C(=O)N4C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To a solution of ethyl 2-oxo-2,3,9,10-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (from Example 211, Step A) (500 mg, 1.6 mmol) in DMF (20 mL) at rt was added NaH (147 mg, 3.6 mmol), MeI (0.25 mL, 4.0 mmol) and stirred at 25° C. for 3 hours. The solution was diluted with water (30 mL) and extracted with EtOAc (2×30 mL). The combined extracts were dried over magnesium sulfate, concentrated, and purified by flash chromatography to afford ethyl 1,3-dimethyl-2-oxo-2,3,9,10-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (350 mg, 64%) as an oil. MS [M+H]+ 328. 1H NMR (CDCl3, 300 MHz): δ 7.18 (d, 1H, J=7.7 Hz), 7.01 (t, 1H, J=7.7 Hz), 6.63 (d, 1H, J=7.7 Hz), 4.90 (m, 1H), 4.51 (m, 1H), 3.20 (m, 5H), 3.49 (m, 1H), 3.42 (s, 3H), 2.91 (m, 1H), 2.80 (m, 1H), 1.61 (d, 3H, J=7.0), 1.28 (t, 3H, J=7.3 Hz) ppm.
Reaction SMILES: [C:1]12[CH2:7][C:4]([CH2:5][CH2:6]1)=[CH:3][CH:2]=2.C([CH:12]=[C:13]([C:17]#[N:18])[C:14]([OH:16])=[O:15])C(C)C.[OH-].[K+]>O>[C:1]12[CH2:7][C:4]([CH2:5][CH2:6]1)=[CH:3][CH:2]=2.[C:17]([C:13](=[CH2:12])[C:14]([OH:16])=[O:15])#[N:18]
Reactant: CC(C)CC=C(C#N)C(=O)O
Agent: C1=C2CCC(=C1)C2
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C=C(C#N)C(=O)O
Temperature: 25 °C

Procedure:
Into a flask fitted with a condenser and magnetic stirring bar is charged 12.3 g (0.05 mole) norbornadiene/isobutyl 2-cyanoacrylic acid adduct and a solution of 4.9 g 86% potassium hydroxide (0.075 mole) in 75 ml. of water. After heating at reflux for 1.5 hours, the solution is cooled to room temperature and extracted with 2 × 25 ml. of hexane to remove any nonsaponified adduct. The aqueous phase is acidified to pH 2 with 6 N hydrochloric acid and the liberated oily product is taken up in 100 ml. ethyl acetate. The extract is filtered to remove some white insoluble solids (0.9g., m.p. 182° C.) and the filtrate washed with 3 × 25 ml. water, 1 × 25 ml. saturated sodium chloride solution, and solvent stripped in vacuo to a pale yellow, viscous oil (8.7 g.). Crystallization of the oily product from benzene/hexane in the cold affords 4.2 g of the norbornadiene/2-cyanoacrylic acid adduct, white crystals, m.p. 83°-86° C. Another 3.0 g. of adduct, m.p. 81°-84° C., is obtained on concentration of the mother liquors and cooling. The combined crops of adduct are recrystallized from 1:2 benzene/hexane to afford 5.9 g of pure adduct, white crystals, m.p. 81°-83° C.
Reaction SMILES: [C:1](#N)[CH3:2].Br[C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH:6]=1.C(N(CC)CC)C>Cl[Pd]Cl.O>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH:1]=[CH2:2])[CH:14]=[CH:13]2
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: CC#N
Agent: Cl[Pd]Cl
Solvent: O
Solvent: CCN(CC)CC
Product: C=Cc1ccc2cc(OC)ccc2c1
Reaction time: 0.5 h

Procedure:
A 20-gallon jacketed stainless steel reactor equipped with a mechanical agitator is charged with 19.45 kg of acetonitrile (ACN) and 12.45 kg of 2-bromo-6-methoxynaphthalene (BMN), and 4.8 g of PdCl2. The reactor is pressured and vented three times with 50 psig nitrogen. The reactor is then charged with 5.3 kg of ACN and 5.64 kg of triethylamine (TEA). The agitator is set at 158 rpm and the reactor is pressured and vented three times with 80 psig nitrogen. The reactor is then purged for ten minutes with nitrogen. Next a mixture of 48.6 g of neomenthyldiphenylphosphine (NMDP) dissolved in 0.35 kg of TEA is charged to the reactor. The agitator is set to 412 rpm and the reactor is heated with steam on the jacket. The reaction temperature is initially in the range of 91-109° C., while the pressure varies from 412-519 psig. The reaction produces a heat kick, and after 30 minutes the temperature rises to 109° C. with 26° C. cooling water on the jacket. The total reaction time is 1.75 hours with a BMN conversion of 100%. The reactor is cooled, vented, and the reactor contents are transferred to a 30-gallon glass lined reactor for workup.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][C:7]=1[O:15][CH3:16].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[S:31](Cl)([CH3:34])(=[O:33])=[O:32]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH:12][S:31]([CH3:34])(=[O:33])=[O:32])=[O:11])=[CH:8][C:7]=1[O:15][CH3:16]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(N)=O)ccc1Cc1ccc(Cl)c(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(C(=O)NS(C)(=O)=O)ccc1Cc1ccc(Cl)c(Cl)c1
Reaction time: 0.33 h

Procedure:
To a solution of 4-(3,4-dichlorobenzyl)-3-methoxybenzamide (Preparation 155, 155 mg, 0.50 mmol) in anyhydrous THF (5 mL) was added 1M LiHMDS (1.25 mL, 1.25 mmol) via syringe. The mixture was stirred for 20 minutes before adding mesyl chloride (0.116 mL, 1.50 mmol) and then stirred for 18 hours at room temperature. The reaction was quenched with the addition of 2M HCl (20 mL), and the aqueous was extracted with EtOAc (3×20 mL). The combined organics were concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with a gradient of 25% EtOAc in heptane to 100% EtOAc. The title compound was obtained as a white solid (40 mg, 21%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:24]=[N:25][N:26]([CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=5)[CH:27]=4)=[CH:21][N:20]([S:36]([C:39]4[CH:45]=[CH:44][C:42]([CH3:43])=[CH:41][CH:40]=4)(=[O:38])=[O:37])[C:17]3=[N:18][CH:19]=2)[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH3:46][C@H:47]1[CH2:49][O:48]1.CCN(C(C)C)C(C)C>C(O)C>[F:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:46][C@H:47]([OH:48])[CH3:49])[CH2:10][CH2:9]2)=[N:6][CH:5]=[C:4]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:24]=[N:25][N:26]([CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=5)[CH:27]=4)=[CH:21][N:20]([S:36]([C:39]4[CH:45]=[CH:44][C:42]([CH3:43])=[CH:41][CH:40]=4)(=[O:37])=[O:38])[C:17]3=[N:18][CH:19]=2)[CH:3]=1
Reactant: C[C@H]1CO1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cnc(N5CCNCC5)c(F)c4)cnc32)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cnc(N5CCN(C[C@@H](C)O)CC5)c(F)c4)cnc32)cc1
Yield: 79 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 5-(5-fluoro-6-(piperazin-1-yl)pyridin-3-yl)-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (product of step 1 of example 179) (170 mg, 0.272 mmol) was alkylated using (S)-2-methyloxirane (32 mg, 0.544 mmol), DIPEA (105 mg, 0.812 mmol) and ethanol (5 mL) to get 147 mg (79% yield) of the titled compound. MS: m/z=684.2 (M+1).
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([CH2:21][OH:22])[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:23]1([C:29](Cl)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[CH2:1]([S:17][CH2:18][CH:19]([CH2:21][O:22][C:29]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCSCC(O)CO
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCSCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 98.3 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar and drying tube, a solution of 70 grams (0.2 mole) (±)-1-S-hexadecylthioglycerol in 300 milliliters of pyridine was added, followed by the addition of 76.0 grams (0.27 mole) triphenylmethyl chloride. The reaction mixture was stirred at room temperature. After 36 hours, the pyridine was removed in vacuo and the resulting oil was dissolved in 450 milliliters of CHCl3. The solution was extracted twice with 500 milliliter portions of 5% HCl, twice with 500 milliliter portions of water and the nonaqueous solution was dried over anhydrous sodium sulfate. The drying agent was filtered, the solvent was removed in vacuo, the residue was dissolved in 500 milliliters of hexanes, and the solution was placed at -5° Centigrade for 24 hours. The resulting precipitate was redissolved in 500 milliliters of acetone and reprecipitated as before. The final precipitate was filtered and dried under vacuum to give 113 grams (94%) of product, (mp 61°-62° Centigrade). 1H-NMR (CDCl3): delta, 0.7-1.7[m, 31H, (CH2)14CH3 ], 2.3-2.8(m, 4H, CH2 --S--CH2), 3.25[d, 2H, CH2 --O--C(C6H5)3 ], 3.6-4.0(m, 1H, CH2 --CH--CH2), 7.0-7.6[m, 15H, C(C6H5)3 ].
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([OH:12])=[CH:4][CH:3]=1.CI.[C:15]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][CH3:15])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1nc(Br)ccc1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1nc(Br)ccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
A mixture of methyl 6-bromo-3-hydroxypicolinate (10.0 g, 43.10 mmol), MeI (12.3 g, 86.66 mmol) and K2CO3 (12.0 g, 86.83 mmol) in DMF (100 mL) was stirred at RT overnight. Then the reaction mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to give methyl 6-bromo-3-methoxypicolinate (4.5 g, yield 42%). 1H-NMR (CDCl3, 400 MHz) δ 7.55 (d, J=8.8 Hz, 1H), 7.24 (d, J=8.8 Hz, 1H), 3.94 (s, 3H), 3.90 (s, 3H). MS (M+H)+: 246/248.
Reaction SMILES: [S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12].[Cl:20]N1C(=O)CCC1=O.C(OCC)(=O)C>CN(C=O)C>[Cl:20][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:1][C:2]=1[NH:10][S:11]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:12])=[O:13]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=S(=O)(Nc1cc2cccnc2s1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=S(=O)(Nc1sc2ncccc2c1Cl)c1ccccc1
Reaction time: 16 h
Yield: 34.5 %

Procedure:
To compound 147-F (0.26 g, 0.643 mmol) in DMF (1 mL) under argon at ambient temperature was added N-chlorosuccinimide (94.4 mg, 0.707 mmol) and the reaction mixture was stirred for 16 h. Ethyl acetate was added, the mixture washed with H2O (2×), brine, evaporated under reduced pressure and purified by reverse phase pHPLC (C18) to afford 0.072 g of compound 813-A as a tan solid. 1H-NMR (DMSO-d6): δ 7.50 (dd, 1H), 7.56-7.65 (m, 2H), 7.65-7.74 (m, 1H), 7.81-7.89 (m, 2H), 8.00 (dd, 1H), 8.58 (dd, 1H).
Reaction SMILES: [C:1]1([C@H:7]([CH2:11][CH:12]=[CH2:13])[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:17])=O>CN(C)C=O.ClCCl>[C:1]1([C@H:7]([CH2:11][CH:12]=[CH2:13])[C:8]([Cl:17])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=CC[C@H](C(=O)O)c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CC[C@H](C(=O)Cl)c1ccccc1
Reaction time: 2 h

Procedure:
Combine (S)-2-phenylpent-4-enoic acid (1.53 g, 8.7 mmol), dichloromethane (10 mL), and dimethylformamide (1 drop). Add oxalyl chloride (1 mL, 11.46 mmol). After 2 hours, evaporate in vacuo to give (S)-2-phenylpent-4-enoyl chloride. Combine with toluene (10 mL) and add, with vigorous stirring, to a cooled (ice bath) aqueous solution of methylamine (2 mL, 40%). After 1 hour, partition the reaction mixture between water and dichloromethane. Separate the layers, dry the organic over MgSO4, filter, and evaporate in vacuo to give a residue. Triturate the residue with hexane to give a solid. Collect the solid by filtration and dry to give (S)-2-phenylpent-4-enoic acid, N-methyl amide: mp; 97-99° C. Rf =0.53 (silica gel, 50% ethyl acetate/hexane).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[N:8]=1)=O.[F:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[CH:29][CH:28]=[C:27]2[NH:34]N>>[F:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[CH:29][CH:28]=[C:27]2[N:34]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: NNc1ccnc2ccc(F)cc12
Reactant: COc1cccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)c1
Product: COc1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccnc4ccc(F)cc34)n2)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-methoxy-phenyl)-1H-pyridazin-4-one (A-5) and (6-fluoro-quinolin-4-yl)-hydrazine according to the method described for example 91. MS: M=414.3 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][C:16]([CH3:21])=[C:17]([CH2:19][OH:20])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1)(=[O:25])=[O:24].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:15][C:16]([CH3:21])=[C:17]([CH2:19][O:20][C:29]3[CH:30]=[CH:31][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:27][CH:28]=3)[N:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: Cc1sc(C2CCN(C(=O)OC(C)(C)C)CC2)nc1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1sc(C2CCN(C(=O)OC(C)(C)C)CC2)nc1COc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4-hydroxymethyl-5-methyl-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.18 g, 0.6 mmol), 4-methanesulfonyl-phenol (0.1 g, 0.6 mmol) and PPh3 (0.19 g, 0.72 mmol) in THF (5 mL) was added diethylazodicarboxylate (DEAD) (0.22 g, 0.72 mmol) at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. The solvent was removed and the residue was purified by flash chromatography on silica gel to afford the desired product. 1H NMR (CDCl3): δ 7.9 (2H, d, J=9 Hz), 7.09 (2H, d, J=9 Hz), 5.2 (2H, s), 4.28-4.10 (2H, m), 3.14-3.04 (1H, m), 3.04 (3H, s), 2.9-2.8 (2H, m), 2.44 (3H, s), 2.1˜2 (2H, m), 1.76-1.64 (2H, m), 1.47 (9H, s).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:14]1([C:20]2[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=2[CH:22]=O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:20]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: O=Cc1ccccc1-c1ccccc1
Product: O=c1cc(N2CCN(Cc3ccccc3-c3ccccc3)CC2)nc[nH]1

Procedure:
6-(4-Biphenyl-2-ylmethyl-piperazin-1-yl)-3H-pyrimidin-4-one was prepared using Procedure B from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 2-phenylbenzaldehyde (available from Aldrich). 1H NMR (400 MHz, CDCl3) δ 2.36-2.39 (m, 4H), 3.43-3.48 (m, 6H), 5.32 (s, 1H), 7.25-7.40 (m, 8H), 7.80 (s, 1H), 12.20 (br s, 1H). Mass spectrum (ES) MH+=347.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])=[N:7][C:6]=2[CH:5]=[C:4]([Cl:18])[CH:3]=1.[CH2:19]([OH:22])[C:20]#[CH:21]>C1(C)C=CC=CC=1.C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Cl:18][C:4]1[CH:3]=[C:2]([C:21]#[C:20][CH2:19][OH:22])[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])=[N:7][C:6]=2[CH:5]=1
Reactant: C#CCO
Reactant: Clc1cc(Br)c2oc(-c3ccccc3Cl)nc2c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: OCC#Cc1cc(Cl)cc2nc(-c3ccccc3Cl)oc12
Reaction time: 6 h
Yield: 85.7 %

Procedure:
A solution of 17.15 g (50 mmol) of 7-bromo-5-chloro-2-(2-chlorophenyl)-benzoxazole and 4.40 ml (75 mmol) of propargylalcohol in 32 ml of toluene and 64 ml of triethylamine was heated under nitrogen to 80-5° C. with 175.4 mg (250 μM) of bis(triphenylphosphine)palladium (II) chloride and 8.6 mg (4.5 μM) of copper (1) iodide. After 6 hours, the solid was filtered off and washed with dichloromethane. The solution was evaporated in vacuo. The residue was dissolved in ethyl acetate, washed with 1 N HCl, sodium bicarbonate solution, and water. The ethyl acetate was removed in vacuo, the residue (15.46 g) was dissolved in dichloromethane and filtered through 60 g of silica gel to give the title compound (13.64 g, 85.8%), mp 165-9° C.
Reaction SMILES: Br[C:2]1[C:3]2[S:9][CH:8]=[C:7](Br)[C:4]=2[S:5][CH:6]=1.[CH3:11][O:12][C:13](=[O:46])[NH:14][C@H:15]([C:19]([N:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[C:26]1[NH:27][C:28]([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)=[CH:29][N:30]=1)=[O:20])[CH:16]([CH3:18])[CH3:17]>>[CH3:11][O:12][C:13](=[O:46])[NH:14][C@H:15]([C:19]([N:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[C:26]1[NH:27][C:28]([C:31]2[CH:32]=[CH:33][C:34]([C:2]3[C:3]4[S:9][CH:8]=[C:7]([C:34]5[CH:35]=[CH:36][C:31]([C:28]6[NH:27][C:26]([C@@H:22]7[CH2:23][CH2:24][CH2:25][N:21]7[C:19](=[O:20])[C@@H:15]([NH:14][C:13]([O:12][CH3:11])=[O:46])[CH:16]([CH3:17])[CH3:18])=[N:30][CH:29]=6)=[CH:32][CH:33]=5)[C:4]=4[S:5][CH:6]=3)=[CH:35][CH:36]=2)=[CH:29][N:30]=1)=[O:20])[CH:16]([CH3:18])[CH3:17]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Reactant: Brc1csc2c(Br)csc12
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3csc4c(-c5ccc(-c6cnc([C@@H]7CCCN7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]6)cc5)csc34)cc2)[nH]1)C(C)C
Yield: 28 %

Procedure:
Compound A26 was synthesized from 3,6-dibromothieno[3,2,b]thiophene (0.335 mmol) and compound 8 (0.738 mmol), following the procedure as described for compound A155. The residue was purified by semi-preparative HPLC to give compound A86 as a yellow solid in 28% yield. 1H NMR (CD3OD, 400 MHz) δ (ppm) 0.92 (d, J=6.69 Hz, 6H), 0.97 (d, J=6.69 Hz, 6H), 1.01 (d, J=6.69 Hz, 2H), 2.01-2.13 (m, 4H), 2.20-2.40 (m, 6H), 3.67 (s, 6H), 3.87-3.93 (m, 2H), 3.99-4.04 (m, 2H), 4.25 (d, J=7.42 Hz, 2H), 5.18-5.21 (m, 2H), 7.37 (s, 2H), 7.79-7.86 (m, 10H); MS (ESI, EI+) m/z=877.5 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17](=[O:19])[CH3:18])=[C:11]([N+:20]([O-])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].C(O)C>[Zn].O>[NH2:20][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:14]([O:15][CH3:16])=[CH:13][C:12]=1[C:17](=[O:19])[CH3:18]
Reactant: COc1cc(C(C)=O)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: COc1cc(C(C)=O)c(N)cc1OCc1ccccc1
Yield: 86 %

Procedure:
A mixture of 1-(4-Benzyloxy-5-methoxy-2-nitro-phenyl)-ethanone (11.94 g 39.6 mmol), ammonium chloride (13.48 g, 250 mmol), zinc powder (65.39 g, 1000 mmol), ethyl alcohol (720 ml) and water (70 ml) was refluxed until completion (5 hours). The mixture was filtered through celite and washed with hot ethyl alcohol. The filtrate was evaporated in vacuum. The residue was taken up in the mixture of chloroform (200 ml), water (200 ml) and the pH of this mixture was set to 8 by adding sodium hydroxide solution. The two layers were separated, the aqueous layer was extracted with chloroform (2×50 ml). The organic layers were combined, washed with water and over Na2SO4, and concentrated to give 9.25 product [C]. Yield 86%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7](=[N:17][OH:18])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)=[N:4][O:5][N:6]=1.[C:19](N1C=CN=C1)(N1C=CN=C1)=[O:20]>O1CCCC1>[NH2:1][C:2]1[C:3]([C:7]2[N:8]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=3)[C:19](=[O:20])[O:18][N:17]=2)=[N:4][O:5][N:6]=1
Reactant: Nc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Temperature: 25 °C
Yield: 102 %

Procedure:
A solution of 4-amino-N-(3-chloro-4-fluorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (80 g, 0.29 mol) [see US Pat. App. Pub. No. 2006/0258719] in tetrahydrofuran (500 mL) was treated with a solution of 1,1′-carbonyldiimidazole (53 g, 0.32 mol) in tetrahydrofuran (200 mL) and heated at reflux for 1 h. The reaction mixture was cooled to 25° C. and concentrated to the point where a large amount of solid precipitated. The heterogeneous mixture was diluted with ethyl acetate (1.5 L) and washed with 1 N HCl (2×300 mL), water (300 mL), and brine (200 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to give the desired product (88 g, quantitative) as an off-white solid. This material was used without further purification. LCMS for C10H6ClFN5O3 (M+H)+: m/z=298.0. 1H NMR (400 MHz, DMSO-d6): δ 7.96 (dd, J=6.6, 2.3 Hz, 1H), 7.69-7.60 (m, 2H), 6.60 (s, 2H).
Reaction SMILES: [C:1]1([CH:7]([NH2:15])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:27][CH2:26][C:25](OC)=[N:24]2)=[CH:19][CH:18]=1>C(O)(C)C>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([CH:23]2[N:24]=[C:25]([NH:15][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:26][CH2:27]2)=[CH:21][CH:22]=1
Reactant: COC1=NC(c2ccc(Br)cc2)CC1
Reactant: NC(Cc1ccccc1)c1ccccc1
Solvent: CC(C)O
Product: Brc1ccc(C2CCC(NC(Cc3ccccc3)c3ccccc3)=N2)cc1
Yield: 55.3 %

Procedure:
A solution of 1,2-diphenyl-ethylamine (500 mg, 2.5 mmol) and 2-(4-bromo-phenyl)-5-methoxy-3,4-dihydro-2H-pyrrole (770 mg, 3.04 mmol) in isopropanol (3 mL) was stirred at 150° C. for 1 h under microwave irradiation (300 W). The resulting suspension was concentrated under reduced pressure. Flash column chromatography purification (NH2-modified SiO2, gradient of cyclohexane/ethyl acetate) of the residue yielded 580 mg (55%) of the desired product as a colorless solid.