Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@:15]2([CH3:16])[C@@H:13]([O:14]2)[CH2:12][C@H:11]([OH:17])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.Cl[Si:24]([CH2:29][CH3:30])([CH2:27][CH3:28])[CH2:25][CH3:26].O>CN(C)C=O>[C:4]([Si:1]([CH3:3])([CH3:2])[O:8][C@@H:9]1[CH2:10][C@@H:11]([O:17][Si:24]([CH2:29][CH3:30])([CH2:27][CH3:28])[CH2:25][CH3:26])[CH2:12][C@H:13]2[C@:15]1([CH3:16])[O:14]2)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC[Si](Cl)(CC)CC
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](O)C[C@@H]2O[C@@]21C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC[Si](CC)(CC)O[C@H]1C[C@@H]2O[C@]2(C)[C@H](O[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
The compound of Example 16D (4.71 g, 18.2 mmol) and imidazole (1.76 g, 25.6 mmol, 1.4 equivalents) were dissolved in 36 mL of dimethylformamide. Then chlorotriethylsilane (3.34 g, 21.9 mmol) was added, and the reaction was stirred at ambient temperature for 2 hours. 125 mL of Water was added to the reaction mixture. Two layers of liquors were obtained and about 6 g of upper layer was separated. Then the lower aqueous layer was extracted three times with 100 mL each of tert-butyl methyl ether. The combined organic layers were washed with 125 mL of 10% aqueous NaCl, dried over MgSO4, filtered and concentrated in vacuo to afford the titled compound (6.71 g, 99%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:11]([C:15]([F:18])([F:17])[F:16])[O:12]2)=[CH:7][CH:6]=1)[CH2:2][CH3:3].[Cl:24]Cl>C(O)(=O)C.[Zn]>[Cl:24][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:5]=1[O:4][CH2:1][CH2:2][CH3:3])[O:12][CH:11]([C:15]([F:18])([F:16])[F:17])[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:9]2
Reactant: CCCOc1ccc2c(c1)OC(C(F)(F)F)C(C(=O)OCC)=C2
Reactant: ClCl
Agent: [Zn]
Solvent: CC(=O)O
Product: CCCOc1cc2c(cc1Cl)C=C(C(=O)OCC)C(C(F)(F)F)O2
Reaction time: 3 h
Yield: 69 %

Procedure:
The ester from Step 1 (0.4 g, 1.2 mmole) in acetic acid (10 mL) was treated with Cl2 (gas) in HOAc solution (Pre-prepared 0.5 M) (7.3 ml, 3.6 mmole). The mixture was stirred for 3 hours. After Cl2 (gas) was blown away, Zn powder (3 eq) was added to the mixture and stirred for 30 min. The Zn salts were removed by filtration and the filtrate was evaporated to dryness. The residue was purified by flash chromatography with 10% ethyl acetate in hexane to give clear oil (0.33 g, 69%). This ester was of suitable purity to use without further purification.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])[CH:2]1[O:4][CH2:3]1.[CH3:13][C:14]([NH2:25])([CH3:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1>>[ClH:12].[OH:4][CH:2]([CH2:1][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])[CH2:3][NH:25][C:14]([CH3:24])([CH3:13])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1
Reactant: COc1ccc(CC(C)(C)N)cc1
Reactant: Clc1ccccc1OCC1CO1
Product: COc1ccc(CC(C)(C)NCC(O)COc2ccccc2Cl)cc1
Product: Cl
Yield: 139.4 %

Procedure:
Using the method of Example 25, supra, 2-chlorophenyl glycidyl ether (1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (1.25 mmol) yielded 279 mg of the title compound as a white solid: GC/EI-MS, m/z (rel. int.) 348 (M-15, 5), 245 (21), 244 (100), 242 (100), 163 (29), 121 (82), 114 (24), 77 (21), 71 (44), 70 (56), 58 (24).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([NH:15][C:16](=[O:24])OC3C=CC=CC=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[NH2:25][NH2:26]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([NH:15][C:16]([NH:25][NH2:26])=[O:24])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCN(NC(=O)Oc3ccccc3)CC2)cc1
Reactant: NN
Solvent: C1COCCO1
Product: COc1ccc(N2CCN(NC(=O)NN)CC2)cc1
Yield: 84 %

Procedure:
A mixture of 8 parts of phenyl [4-(4-methoxyphenyl)-1-piperazinyl]carbamate, 15 parts of hydrazine and 50 parts of 1,4-dioxane is stirred and refluxed for 4 hours. The reaction mixture is evaporated. The residue is triturated in 2-propanol. The product is filtered off and crystallized from 1-butanol, yielding 6.5 parts (84%) of N-[4-(4-methoxyphenyl)-1-piperazinyl]hydrazinecarboxamide.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].C([C:14]1[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=1)#N>>[CH3:21][S:20][C:17]1[CH:18]=[CH:19][C:14]([C:1]2[NH:2][C:3](=[O:11])[C:4]3[C:5]([CH:10]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[CH:15][CH:16]=1
Reactant: CSc1ccc(C#N)cc1
Reactant: CNC(=O)c1ccccc1C
Product: CSc1ccc(-c2cc3ccccc3c(=O)[nH]2)cc1
Yield: 46.7 %

Procedure:
According to the method of Example 10-1, N-methyl-2-methylbenzamide (5.97 g) and 4-cyanothioanisole (5.97 g) were reacted, to give 3-(4-methylthiophenyl)isoquinolin-1-one (5.00 g).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:3]=1[CH2:4][CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]12.C([Sn](CCCC)(CCCC)[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)CCC>C1(C)C=CC=CC=1.[Pd].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.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>[O:10]=[C:8]1[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]2[C:18]3[C:3]([CH2:4][CH:5]2[CH2:9]1)=[C:2]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[CH:21]=[CH:20][CH:19]=3
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: CC(C)(C)OC(=O)N1C(=O)CC2Cc3c(Br)cccc3C21
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C(=O)CC2Cc3c(-c4cccnc4)cccc3C21
Reaction time: 0.08 h

Procedure:
Tert-butyl 5-bromo-2-oxo-3,3a,4,8b-tetrahydroindeno[1,2-b]pyrrole-1-carboxylate (Example 1. Step 3, 0.500 g, 1.42 mmol), tributyl(3-pyridyl)stannane (0.784 g, 2.12 mmol) and tetrakis(triphenylphosphine) palladium (0.164 g, 0.142 mmol) were dissolved in toluene. The mixture was irradiated in the microwave at 160° C. and normal absorption level for 5 minutes. The toluene was removed and the mixture was taken up in acetonitrile and n-hexan. The hexane layer was extracted again with acetonitrile and the combined acetonitrile layers were dried over sodium sulphate and evaporated. The crude was purified by flash chromatography to give tert-butyl 2-oxo-5-(3-pyridyl)-3,3a,4,8b-tetrahydroindeno[1,2-b]pyrrole-1-carboxylate E11 (0.409 g, 82%); LCMS (method A) RT 1.45 min; ES+351 (M+H+). The compounds E9-E13 were prepared according to this procedure.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16](I)=[CH:17][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)=[CH:17][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cccnc1
Reactant: Ic1cnc2c(c1)N(Cc1ccccc1)CCN2
Product: c1ccc(CN2CCNc3ncc(-c4cccnc4)cc32)cc1
Yield: 23 %

Procedure:
1-Benzyl-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (30 mg) was reacted with pyridine 3-boronic acid as in General Procedure 4A to give the title compound as a light yellow film (23% yield). M.p. (film), LCMS: m/z=303.40 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.41-3.44 m, 2H), 3.60-3.63 (m, 2H), 4.49 (s, 2H), 6.80 (s, 1H), 5.40 (bs, 1H), 6.80 (s, 1H), 7.27-7.42 (m, 5H), 7.64 (s, 1H), 7.65 (d, J=7.8 Hz, 1H), 8.48 (d, J=4.8 Hz, 1H), 8.63 (s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]3)[NH:12][C:11](=[O:27])[C:10]=2[CH:28]=1.[OH-].[Na+]>O.O1CCOCC1>[C:22]([O:21][C:19]([N:15]1[CH2:16][CH2:17][CH2:18][C:13]2([NH:12][C:11](=[O:27])[C:10]3[CH:28]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:29])=[O:2])[CH:7]=[CH:8][C:9]=3[O:26]2)[CH2:14]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)NC1(CCCN(C(=O)OC(C)(C)C)C1)O2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC2(C1)NC(=O)c1cc(/C=C/C(=O)O)ccc1O2
Yield: 92.2 %

Procedure:
A solution of (±)-(E)-3-{1′-tert-butoxycarbonyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-acrylic acid methyl ester (Intermediate 5, Step B, 270 mg, 0.67 mmol) in water (3 ml) and dioxane (6 ml) was treated with 1 M NaOH (0.75 ml) as described in Example 30, Step A to give (±)-(E)-3-{1′-tert-butoxycarbonyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,3′-piperidin]-6-yl}-acrylic acid (240 mg) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:11]2[N:10]3[CH2:12][CH2:13][CH2:14][CH:9]3[CH2:8][O:7][C:6]=2[CH:5]=[C:4]([NH2:15])[CH:3]=1.C[Al](C)C.N#N.[NH:22](/[C:26](/[CH3:32])=[CH:27]\[C:28](OC)=[O:29])[C:23]([CH3:25])=O>C(Cl)Cl>[F:1][C:2]1[C:11]2[N:10]3[CH2:12][CH2:13][CH2:14][CH:9]3[CH2:8][O:7][C:6]=2[CH:5]=[C:4]([N:15]2[C:28](=[O:29])[CH:27]=[C:26]([CH3:32])[N:22]=[C:23]2[CH3:25])[CH:3]=1
Reactant: COC(=O)/C=C(/C)NC(C)=O
Reactant: Nc1cc(F)c2c(c1)OCC1CCCN21
Agent: C[Al](C)C
Agent: N#N
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2cc(F)c3c(c2)OCC2CCCN32)c(C)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 33 %

Procedure:
To a solution of 9-fluoro-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazin-7-amine (2.00 g, 9.61 mmol) in anhydrous CH2Cl2 (50 mL) was added trimethylaluminum (48 mL, 48 mmol, 1 M in heptane) slowly under N2. Upon the end of addition the mixture was stirred at rt for 40 min, followed by addition of a solution of methyl 3-acetaminocrotonate (2.66 g, 16.92 mmol) in anhydrous CH2Cl2 (30 mL) dropwise. The reaction mixture was stirred at rt for another 5 h, then quenched with an appropriate amount of water. The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a white solid (1.00 g, 33.0%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: CS([C:4]1[N:9]=[C:8]([N:10]2[C:18]3[C:13](=[C:14]([O:19][CH2:20][CH2:21][CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)[CH:7]=[CH:6][N:5]=1)=O.C([O-])(=O)C.[OH:31][C:32]([CH:35]1[CH2:40][CH2:39][CH:38]([NH3+:41])[CH2:37][CH2:36]1)([CH3:34])[CH3:33].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH3:26][S:23]([CH2:22][CH2:21][CH2:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[CH:12]=[CH:11][N:10]2[C:8]1[CH:7]=[CH:6][N:5]=[C:4]([NH:41][CH:38]2[CH2:39][CH2:40][CH:35]([C:32]([OH:31])([CH3:33])[CH3:34])[CH2:36][CH2:37]2)[N:9]=1)(=[O:25])=[O:24]
Reactant: CS(=O)c1nccc(-n2ccc3c(OCCCS(C)(=O)=O)cccc32)n1
Reactant: CC(C)(O)C1CCC([NH3+])CC1
Agent: CC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(O)C1CCC(Nc2nccc(-n3ccc4c(OCCCS(C)(=O)=O)cccc43)n2)CC1
Temperature: 126 °C
Yield: 57.4 %

Procedure:
1-(2-Methanesulfinyl-pyrimidin-4-yl)-4-(3-methanesulfonyl-propoxy)-1H-indole (538 mg, 1.4 mmol), 4-(2-hydroxyprop-2-yl)-cyclohexylammonium acetate (400 mg, 2 mmol), and DIEA (0.8 mL, 5 mmol) were combined in NMP (10 mL) and heated to 126° C. in a sealed tube for 4 h, cooled, and partitioned between water and EtOAc. The organic layer was separated and washed twice with water, dried over sodium sulfate, filtered and purified by flash chromatography (SiO2) with 3:97 MeOH/DCM, and recrystallized from MeOH/DCM, triturated with EtOAc and solvent evaporated to yield 2-(4-{4-[4-(3-methanesulfonyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-propan-2-ol (Compound 166, 391 mg, 59%) as a white powder.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([CH3:21])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:20])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17].[P:22]([O:29]CC)([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25]>>[CH2:24]([O:23][P:22]([CH2:2][CH2:3][CH:4]([CH3:21])[CH2:5][CH2:6][CH2:7][CH:8]([CH3:20])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])([O:26][CH2:27][CH3:28])=[O:29])[CH3:25]
Reactant: CCOP(OCC)OCC
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCBr
Product: CCOP(=O)(CCC(C)CCCC(C)CCCC(C)CCCC(C)C)OCC
Temperature: 150 °C
Reaction time: 18 h
Yield: 93.6 %

Procedure:
A mixture of 21.69 g (60 mmol) of 1-bromo-3,7,11,15-tetramethylhexadecane and 25 g (150 mmol) of triethyl phosphite was heated at 150° C. After 18 h, an additional 20 g (120 mmol) of triethyl phosphite was added, and heating was continued for 24 h. Diethyl ethylphosphonate and other volatiles were distilled, bp 30-50° C. at 0.05 mm Hg, and bulb-to-bulb distillation of the concentrate provided 23.51 g (94%) of 1-(diethylphosphono)-3,7,11,15-tetramethylhexadecane as a clear, colorless liquid, bp 190-230° C. at 0.05 mm Hg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42][C:43](=[O:49])OC(Cl)(Cl)Cl)Cl.[N:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[S:57][CH2:58][CH2:59]CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:42][CH2:40][CH2:59][CH2:58][S:57][C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][N:51]=2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: OCCCSc1ccccn1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCCSc4ccccn4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Yield: 14 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (80 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (111 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-(2-pyridylsulfanyl)-1-propanol (63 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (18 mg, yield 13%).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=O)[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:6]1[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1nc(C(F)(F)F)cc(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Cc1nc(Cl)cc(C(F)(F)F)n1
Yield: 91 %

Procedure:
2-Methyl-6-trifluoromethyl-4H-pyrimidin-4-one of Example 4 (2.00 g, 11.2 mmol) was mixed with phosphorus oxychloride (10 mL) and N,N-dimethylaniline (2 mL), and refluxed for 3 h. The dark solution was poured into crushed ice and extracted with Et2O. The organic layer was washed with H2O (twice), dried over Na2SO4, then evaporated to dryness to afford 2.00 g (91%) of an oil.
Reaction SMILES: [C:1]([C:4]1[NH:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[Br:9]N1C(=O)CCC1=O>O1CCCC1.CO>[Br:9][C:6]1[NH:5][C:4]([C:1](=[O:3])[CH3:2])=[CH:8][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1ccc[nH]1
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)c1ccc(Br)[nH]1
Temperature: 25 °C
Yield: 22.4 %

Procedure:
2-Acetylpyrrole (2.00 g, 18.3 mmol) was dissolved in a mixed solvent of tetrahydrofuran (100 mL) and methanol (50 mL), and N-bromosuccinimide (3.26 g, 18.3 mmol) was added with stirring at room temperature under nitrogen atmosphere. After stirring for 1 hour, the solvent was distilled off under reduced pressure. A saturated aqueous sodium hydrogencarbonate solution (200 mL) was added, and extraction was carried out with ethyl acetate (300 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-20%) to afford the desired compound (770 mg, yield 22%) as a white solid.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:11][CH3:12])[C:5]2=[N:4][CH:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:12][NH:11][C:10]1[C:5]2[N:6]([C:2]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:3][N:4]=2)[CH:7]=[CH:8][N:9]=1
Reactant: CNc1nccn2c(Br)cnc12
Reactant: OB(O)c1ccccc1
Product: CNc1nccn2c(-c3ccccc3)cnc12
Yield: 63 %

Procedure:
Using Method 1, the title compound was prepared from (3-bromo-imidazo[1,2-a]pyrazin-8-yl)-methyl-amine (Example 1) and phenylboronic acid (from Aldrich) in 63% yield.
Reaction SMILES: [C:1]([OH:24])(=[O:23])[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][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(O)(=O)CCCCCCCCCCCCCCCCC.[OH-].[Na+:46].[N+]([O-])(O)=O>O>[C:1]([O-:24])(=[O:23])[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][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Na+:46]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: CCCCCCCCCCCCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=[N+]([O-])O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)[O-]
Temperature: 55 °C

Procedure:
Behenic acid of 32.4 g, 9.9 g of alginic acid and 5.6 g of stearic acid were dissolved in 945 ml of pure water at 90° C. Next, 98 ml of 1.5 mol/L sodium hydroxide solution was added thereto with high speed stirring. Then, 0.93 ml of concentrated nitric acid was added thereto, cooled to 55° C. and stirred for 30 min. to obtain the sodium behenate solution.
Reaction SMILES: [F:1][C:2](=[CH2:6])[C:3](Cl)=[O:4].[Cl:7][C:8]([Cl:12])([Cl:11])[CH2:9][OH:10].C(N(CC)CC)C>O>[F:1][C:2](=[CH2:6])[C:3]([O:10][CH2:9][C:8]([Cl:12])([Cl:11])[Cl:7])=[O:4]
Reactant: OCC(Cl)(Cl)Cl
Reactant: C=C(F)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: C=C(F)C(=O)OCC(Cl)(Cl)Cl
Reaction time: 3 h

Procedure:
12 g of 2-fluoroacryloyl chloride and 26 g of 2,2,2-trichloroethanol were introduced into a round-bottomed flask placed in an ice bath. 17 g of triethylamine were added portionwise to the reaction mixture. After reacting for an additional 3 h, approximately 50 ml of water were added. The aqueous and organic phases were subsequently separated and the organic phase was analysed by GC. The conversion of the 2,2,2-trichloroethanol was 52%. The yield of ester, based on the amount of 2-fluoroacrylic acid employed in the first stage, was 67%.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[C:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:9])[CH:6]([CH3:8])[CH3:7]>O.C(O)(=O)C>[N:1](=[C:10]([C:5](=[O:9])[CH:6]([CH3:8])[CH3:7])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[OH:3]
Reactant: O=N[O-]
Reactant: CCOC(=O)CC(=O)C(C)C
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=NO)C(=O)C(C)C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
A solution of sodium nitrite (43.8 g.) in water (92 ml.) was added dropwise, with stirring, to a solution of ethyl isobutyrylacetate (100.3 g.) in acetic acid (80 ml.) at 0°. After stirring at 0° for 30 minutes then at room temperature for 3 hours, water (100 ml.) was added and the mixture extracted with ether. Th extracts were washed with water, saturated sodium bicarbonate solution and water. After drying (CaSO4), the solution was evaporated to give ethyl 2-oximino-4-methyl-3-oxopentanoate (112 g.) as a crude oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([Cl:16])[N:3]=1.[CH3:17][NH:18][CH2:19][CH2:20][C:21]#[N:22].CN(C)P(N(C)C)(N(C)C)=O>C(O)(C)C>[ClH:16].[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:18]([CH2:19][CH2:20][C:21]#[N:22])[CH3:17])[N:3]=1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: CNCCC#N
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)O
Product: COc1cc2nc(N(C)CCC#N)nc(N)c2cc1OC
Product: Cl
Temperature: 100 °C
Reaction time: 9 h
Yield: 63.8 %

Procedure:
50 gms, 0.208 moles of 4-amino-2-chloro-6,7-dimethoxyquinazoline and 21.2 gms, 0.252 moles of 3-methylaminopropionitrile were charged in a round bottom flask containing 350 ml hexamethylphosphoramide. The reaction mass was stirred at about 100° C. for 9 hours, cooled to a temperature of 25° C. and then charged with 250 ml isopropanol. The reaction mass was further stirred for 15 minutes, filtered and washed with 50 ml isopropanol and subjected to drying at 50° C. for 7-8 hours to yield N-(4-amino-6,7-dimethoxyquinazol-2-yl)-N-methyl-2-cyanoethylamine hydrochloride (43 gms).
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].C(O[CH:10]([O:21]CCCC)[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[N+:18]([O-])=O)CCC.[Cl-].[NH4+]>O1CCCC1>[F:17][C:15]1[CH:14]=[C:13]2[C:12](=[C:11]([CH:10]=[O:21])[CH:16]=1)[NH:18][CH:2]=[CH:1]2
Reactant: C=C[Mg]Br
Reactant: CCCCOC(OCCCC)c1cc(F)ccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1cc(F)cc2cc[nH]c12
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 56.1 %

Procedure:
Add vinylmagnesium bromide (1 M in tetrahydrofuran, 85.2 mL, 85.2 mmol) dropwise to a solution of 2-dibutoxymethyl-4-fluoro-1-nitro-benzene (8.5 g, 28.4 mmol) in tetrahydrofuran (250 mL) at −78° C. Warm the reaction mixture −45° C. to −50° C. for 30 minutes, cool to −78° C., and add vinylmagnesium bromide (1 M in tetrahydrofuran, 85.2 mL, 85.2 mmol) drop wise. Warm the reaction mixture to −45° C. to −50° C. for 20 minutes, then add saturated aqueous ammonium chloride (300 mL). Warm the mixture to room temperature and extract with diethyl ether (200 mL×2). Wash the combined organic phases with saturated aqueous sodium chloride (400 mL×2), dry over sodium sulfate, and concentrate under reduced pressure. Dissolve the residue in tetrahydrofuran (100 mL), add 0.5 N HCl (10 mL), and stir for 20 minutes. Dilute the mixture with diethyl ether (200 mL), wash sequentially with saturated aqueous sodium bicarbonate (200 mL×3) and saturated aqueous sodium chloride (200 mL×2). Dry the organic phase over sodium sulfate and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 5% to 10% ethyl acetate in hexanes to provide the desired compound as a pale yellow solid (2.6 g, 56%).
Reaction SMILES: C([O:4][C:5]1[C:14]([O:15]C(=O)C)=[CH:13][C:12]2[C:7](=[CH:8][C:9]([S:19](Cl)(=[O:21])=[O:20])=[CH:10][CH:11]=2)[CH:6]=1)(=O)C.[NH3:23].[Na+].C(OC1C=C2C(=CC=1OC(=O)C)C=C(S([O-])(=O)=O)C=C2)(=O)C>O1CCCC1>[OH:4][C:5]1[C:14]([OH:15])=[CH:13][C:12]2[C:7](=[CH:8][C:9]([S:19]([NH2:23])(=[O:21])=[O:20])=[CH:10][CH:11]=2)[CH:6]=1
Reactant: CC(=O)Oc1cc2ccc(S(=O)(=O)Cl)cc2cc1OC(C)=O
Reactant: N
Agent: CC(=O)Oc1cc2ccc(S(=O)(=O)[O-])cc2cc1OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc2cc(O)c(O)cc2c1
Reaction time: 8 h

Procedure:
A solution of 20.0 g. (0.0583 mole) of 2,3-diacetoxy-7-naphthalenesulfonyl chloride in 300 ml. of tetrahydrofuran was treated with 8.7 ml. (0.13 mole) of aqueous 28% ammonia. The solid (9.9 g., infrared spectrum identical with that of 6,7-diacetoxy-2-naphthalenesulfonic acid sodium salt) was removed by filtration and the filtrate evaporated to dryness. The residue was dissolved in 150 ml. of ethyl acetate. The residue from evaporation of the dried (anhydrous sodium sulfate) solution was slurried with four 100-ml. portions of ether and then dissolved in 150 ml. of 3A alcohol. The solution was saturated with hydrogen chloride, allowed to stand overnight, and then concentrated at the water pump to give 9.7 g. of colorless residue. Recrystallization from 50 ml. of water gave 5.1 g. (37%) of pale violet solid, m.p. 218°-228° C.