Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:33][C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=1[F:42])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:29]([F:32])([F:31])[F:30])=[N:19][C:20]([C:21]([N:23]3[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]3)=[O:22])=[C:14]2[CH2:13]1)=[O:11])(C)(C)C.[ClH:44]>C(OCC)(=O)C>[ClH:44].[NH2:7][C@H:8]([CH2:33][C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=1[F:42])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:29]([F:32])([F:31])[F:30])=[N:19][C:20]([C:21]([N:23]3[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]3)=[O:22])=[C:14]2[CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CC[C@@H](O)C3)c2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CC[C@@H](O)C3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 72 %

Procedure:
(R)-[3-[1-((R)-3-Hydroxy-pyrrolidine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 14a (90 mg, 0.15 mmol) was added to a solution of 2.3 N hydrochloric acid in 10 mL of ethyl acetate. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-3-amino-1-[1-((R)-3-hydroxy-pyrrolidine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-4-(2,4,5-trifluoro-phenyl)-butan-1-one hydrochloride 14 (60 mg, yield 72%) as a white solid.
Reaction SMILES: C([Li])CCC.N1CCOCC1.[O:12]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13]1.C([Li])(CC)C.I[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].Cl>CCCCCC.O1CCCC1.C1CCCCC1>[CH2:25]([C:16]1[O:12][CH:13]=[C:14]([CH:17]=[O:18])[CH:15]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCI
Reactant: O=Cc1ccoc1
Agent: Cl
Agent: [Li]C(C)CC
Agent: [Li]CCCC
Solvent: C1COCCN1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCc1cc(C=O)co1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
n-Butyl lithium (a 2.5M solution in hexane; 4.37 ml, 10.9 mmol) was added to a solution of morpholine (0.91 ml, 10.4 mmol) in tetrahydrofuran (40 ml) at -78° under argon. After 20 min., 3-furaldehyde (0.9 ml, 10.4 mmol) was added. After another 20 min., sec-butyl lithium (a 1.3M solution in cyclohexane; 8.4 ml, 10.9 mmol) was added dropwise and stirring continued at -78° for 4 hours before 1-iodooctane (2.07 ml, 11.4 mmol) was added. Stirring was continued overnight (17 hours) while the cooling bath was allowed to attain room temperature. The solution was poured into ice cold 10% (v/v) hydrochloric acid (15 ml) and after stirring at 0° for 10 min., the layers were separated. The aqueous phase was extracted with diethyl ether. All the organic phases were combined, dried (magnesium sulfate) and evaporated to give an oil, which was purified by flash chromatography on silica using 10% ethyl ether/hexane. Fractions with Rf of about 0.23 on evaporation afforded the title compound as colorless needles, m.p. 25° (hexane).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]1[C@@H:18]2[C@H:12]([CH:13]=[CH:14][C:15]3[C:16]4[N:17]2[C:19]2[CH:28]=[CH:27][N:26]=[CH:25][C:20]=2[C:21]=4[CH2:22][CH2:23][CH:24]=3)[CH2:11][CH2:10][CH2:9]1.C(Cl)(Cl)Cl.[CH:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH:36]=[CH:35][CH2:34]1>O>[CH:33]1([C:39]([CH:10]2[CH2:11][CH:12]3[CH:13]=[CH:14][C:15]4[C:16]5[N:17]([C:19]6[CH:28]=[CH:27][N:26]=[CH:25][C:20]=6[C:21]=5[CH2:22][CH2:23][CH:24]=4)[CH:18]3[CH2:8][CH2:9]2)=[O:40])[CH2:38][CH2:37][CH:36]=[CH:35][CH2:34]1
Reactant: O=C(Cl)C1CC=CCC1
Reactant: C1=C[C@@H]2CCCC[C@H]2n2c3c(c4cnccc42)CCC=C13
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(C1CC=CCC1)C1CCC2C(C=CC3=CCCc4c3n2c2ccncc42)C1

Procedure:
Triethylamine (10 ml.) was added with stirring to a solution of 5.5 g. (±)-trans-1,2,3,4,4a,8,9,14a-octahydropyrido[4',3':2,3]indolo[1,7-ab][1]benzazepine in 100 ml. chloroform, followed by addition, with stirring, of 5.76 g. (0.04 moles) 3-cyclohexene-1-carbonyl chloride in 10 ml. chloroform. The mixture was refluxed 2 hours then cooled and water was added. The organic layer was separated, dried over K2CO3, and evaporated to dryness in vacuo. Trituration of the residual oil in hexane gave (±)-trans-3-[(3-cyclohexen-1-yl)carbonyl]-1,2,3,4,4a,8,9,14a-octahydropyrido[4',3':2,3]indolo[1,7-ab][1]benzazepine, m.p. 156.5°-158.5° .
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:24](OCC)(=[O:26])[CH3:25].O>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH2:12][CH2:13][N:14]([CH2:25][CH2:24][OH:26])[CH2:15][CH:16]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1
Reactant: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: OCCN1CC=C(c2c[nH]c3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 6-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (1.0 g, 0.00462 mol) and triethylamine (0.77 ml, 0.00555 mol) in DMF (60 ml), was added dropwise under nitrogen 2-bromoethanol (0.42 ml, 0.00555 mol) then allowed to stir at room temperature overnight. Workup involved addition of ethyl acetate (80 ml) and water (50 ml), the organic layer was washed with water (4×50 ml). The organic layer was dried (MgSO4) and concentrated in vacuo to afford 2-(4-(6-fluoro-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)ethanol as a yellow solid 1.02 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C@@H:10]([N:12]=[N+]=[N-])[CH3:11]>CCOC(C)=O.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C@@H:10]([NH2:12])[CH3:11]
Reactant: C[C@@H](Cc1cc(F)ccc1Cl)N=[N+]=[N-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@H](N)Cc1cc(F)ccc1Cl
Yield: 74.6 %

Procedure:
To a solution of (1S)-2-(2-chloro-5-fluorophenyl)-1-methylethyl azide (1.10 g, 5.15 mmol) in 100 mL of EtOAc was added Pd/C (300 mg of 10% Pd) and the mixture was hydrogenated under hydrogen balloon for 30 min. The catalyst was removed by filtration through celite, then passed through silicagel plug eluting first with EtOAc (40 mL), then MeOH/EtOAc/NH4OH 20:75:5 (120 mL). The fraction with product was evaporated to give (1S)-2-(2-chloro-5-fluorophenyl)-1-methylethylamine (721 mg, 67%) as pale yellow oil. ESI-MS: m/z (MH+) 188.3. 1H NMR (300 MHz, CDCl3): δ 7.30 (m, 1H), 6.86-6.97 (m, 2H), 3.26 (m, 1H), 2.66-2.84 (m, 2H), 1.40 (s, 2H), 1.15 (d, J=6.42 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:5]([C:6]([OH:8])=O)=[C:4]([F:12])[CH:3]=1.[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:18][CH:19]=1>>[Br:1][C:2]1[CH:3]=[C:4]([F:12])[C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:17]3[CH:16]=[CH:15][C:14]([CH3:13])=[CH:19][N:18]=3)[CH2:21][CH2:22]2)=[O:8])=[C:9]([F:11])[CH:10]=1
Reactant: Cc1ccc(N2CCNCC2)nc1
Reactant: O=C(O)c1c(F)cc(Br)cc1F
Product: Cc1ccc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)nc1
Yield: 66.3 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 90 and using 4-bromo-2,6-difluorobenzoic acid (1.56 g) and 1-(5-methylpyridin-2-yl)piperazine (1.06 g) described in Preparation Example 183, the title compound (1.57 g) was obtained.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.Cl.[CH3:27][S:28]([C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34])(=[O:30])=[O:29].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(C)([O-])C.[Na+]>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([NH:34][C:33]3[CH:35]=[CH:36][CH:37]=[C:31]([S:28]([CH3:27])(=[O:30])=[O:29])[CH:32]=3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: CS(=O)(=O)c1cccc(N)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3cccc(S(C)(=O)=O)c3)nc12
Temperature: 140 °C
Yield: 33.6 %

Procedure:
A mixture of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (150 mg, 351 mol), 3-(methylsulfonyl)aniline hydrochloride (109 mg, 526 mol), BINAP (10.9 mg, 17.5 mol), palladium (II) acetate (19.7 mg, 87.7 mol) and sodium tert-butoxide (101 mg, 1.05 mmol, Eq: 3) in DMF (1 mL) and toluene (500 μL) was heated in a microwave at 140° C. for 20 min. The reaction mixture was diluted with water then extracted into ethyl acetate (3×). The combined organic extracts were washed with brine then dried over magnesium sulfate. Purification by chromatography (silica, 20-50% ethyl acetate in hexanes) gave N-tert-butyl-2-(3-(methylsulfonyl)phenylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (61 mg, 118 mol, 34%) as a brown gum. (EI/CI) m/z: 518.3 [M+H].
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:14])/[CH:9]=[CH:10]\[C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(=O)(O)(O)O>>[C:1]1([N:7]2[C:8](=[O:14])[CH:9]=[CH:10][C:11]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)/C=C\C(=O)Nc1ccccc1
Agent: O=P(O)(O)O
Product: O=C1C=CC(=O)N1c1ccccc1
Temperature: 210 °C

Procedure:
The slurry containing the N-phenyl maleinamic acid and 10 g of ortho-phosphoric acid added thereto were heated at 210° C. for three hours. The resultant reaction mixture was cooled to 30° C., washed with water, and distilled under a vacuum to expel tetrahydronaphthalene and obtain 78 g of N-phenyl maleimide crystals. By liquid chromatography, the crystals were found to have purity of 87.3% by weight, indicating the yield thereof to be 73.2 mol %.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6](Cl)[N:5]2[N:15]=[CH:16][CH:17]=[C:4]2[N:3]=1.C(O)(=O)C.CO>C1COCC1>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]2[N:15]=[CH:16][CH:17]=[C:4]2[N:3]=1
Reactant: Clc1nc2ccnn2c(Cl)c1-c1ccccc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: Clc1nc2ccnn2cc1-c1ccccc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of 1 g 5,7-dichloro-6-phenylpyrazolo[1,5-a]pyrimidine, 0.5 mL glacial acetic acid, 1 mL methanol, 6 mL THF and 730 mg of Zn/Cu pair were stirred for 3 h at 50° C. The mixture was filtered through celite, evaporated to dryness and the residue was purified on silica gel (hexanes/ethyl acetate) to yield 550 mg of a 1:1 mixture of the desired product and the starting material, which was used without further purification.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[CH:9]=2)[N:4]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:3]=1.[CH3:40][C:41]1[C:45](B2OC(C)(C)C(C)(C)O2)=[C:44]([CH3:55])[N:43]([CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([O:63][C:64]([F:67])([F:66])[F:65])[CH:58]=2)[N:42]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[CH3:40][C:41]1[C:45]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)=[CH:13][CH:12]=4)[CH:9]=3)[N:4]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:3]=2)=[C:44]([CH3:55])[N:43]([CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([O:63][C:64]([F:66])([F:67])[F:65])[CH:58]=2)[N:42]=1
Reactant: Cc1nn(Cc2cccc(OC(F)(F)F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(OC(F)(F)F)c4)c3C)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Yield: 77 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (intermediate 41) (150 mg, 0.227 mmol) was coupled with 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(3-(trifluoromethoxy)benzyl)-1H-pyrazole (Intermediate 44) (135.6 mg, 0.34 mmol) in sodium carbonate (72.4 mg, 0.68 mmol), PdCl2(dppf)Cl2 (8 mg, 0.011 mmol), toluene/ethanol/water (3/5/1 ml) to give 140 mg (76.9% yield) of titled compound. MS: m/z=801.3 (M+1).
Reaction SMILES: C(N(CC)CC)C.[C:8]([NH2:14])(=[O:13])[CH2:9][C:10]([CH3:12])=[O:11].Cl[S:16](F)(=[O:18])=[O:17]>>[CH3:12][C:10]1[O:11][S:16](=[O:18])(=[O:17])[NH:14][C:8](=[O:13])[CH:9]=1
Reactant: O=S(=O)(F)Cl
Reactant: CC(=O)CC(N)=O
Solvent: CCN(CC)CC
Product: CC1=CC(=O)NS(=O)(=O)O1
Reaction time: 2 h
Yield: 46 %

Procedure:
A mixture, with a total volume of 50 ml, of 40.4 g (0.4 mol) of triethylamine and liquid SO2 was added dropwise, at -10° C., to a solution of 20.2 g (0.2 mol) of acetoacetamide and 23.7 g (0.2 mol) of chlorosulfonyl fluoride in 70 ml of liquid SO2. The mixture was stirred for 2 hours and the liquid SO2 was then distilled off, a vacuum being applied at the end. The residue was added dropwise to 400 ml of aqueous NaOH, acidified with concentrated hydrochloric acid, with ice-cooling, and extracted with ethyl acetate. After treatment of the ethyl acetate phase with animal charcoal and Na2SO4, the extract was evaporated in vacuo. 15 g (approx. 20% of theory) of 6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide were obtained.
Reaction SMILES: [BH4-].[Na+].[C:3]([N:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]>CO.O.[Cl-].[Na+].O>[OH:16][CH:13]1[CH2:12][CH2:11][N:10]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(O)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Sodium borohydride (0.95 g, 25 mmol) was added to a solution of 1-Boc-4-piperidone (2.50 g, 12.5 mmol) in MeOH (25 mL) at 0° C. The resulting mixture was stirred at 0° C. for 2 hours, then room temperature for 2 hours. The mixture was diluted with water (100 mL) and brine (100 mL) then extracted with EtOAc (2×150 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to give the title compound A110 as a thick colorless oil (2.47 g, 98%); 1H NMR (400 MHz, CDCl3) δ 3.91-3.79 (m, 3H), 3.02 (m, 2H), 1.93-1.78 (m, 2H), 1.56 (d, J=4.2 Hz, 1H), 1.52-1.40 (m, 11H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([P-:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[K+].F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]1[C:28]([CH:29]([CH3:31])[CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=1[CH:32]([CH3:34])[CH3:33]>O1CCOCC1>[C:8]1([P:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][C:23]2[C:28]([CH:29]([CH3:31])[CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[CH:32]([CH3:34])[CH3:33])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)c1cccc(C(C)C)c1Nc1ccccc1F
Reactant: c1ccc([P-]c2ccccc2)cc1
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)c1cccc(C(C)C)c1Nc1ccccc1P(c1ccccc1)c1ccccc1

Procedure:
A 250-mL Schlenk flask equipped with a condenser was flashed with nitrogen thoroughly. To this flask was added KPPh2 (73 mL, 0.5 M in THF solution, Aldrich, 36.9 mmol). THF was removed in vacuo and a solution of N-(2-fluorophenyl)-2,6-diisopropylaniline (10 g, 36.9 mmol) in 1,4-dioxane (40 mL) was added with a syringe. The transparent, ruby reaction solution was heated to reflux for 5 d, during which time the reaction condition was monitored by 31P {1H} NMR spectroscopy. All volatiles were removed from the resulting orange solution under reduced pressure and degassed deionized water (100 mL) was added. The product was extracted with deoxygenated dichloromethane (100 mL). The dichloromethane solution was separated from the aqueous layer, from which the product was further extracted with dichloromethane (20 mL×2). The combined organic solution was dried over MgSO4 and filtered. All volatiles is were removed in vacuo to yield the product as pale yellow oil. The product was purified by washing it with boiling EtOH (10 mL×4) until it became white powder; yield 15.2 g (94%). 1H NMR (CDCl3, 200MHz) δ7.39 (m, 10, PC6H5), 7.0-7.22 (m, 4, Ar), 6.82 (m, 1, Ar), 6.65 (t, 1, Ar), 6.15 (m, 1, Ar), 5.95 (d, 1, JHP=8, NH), 2.90 (septet, 2, CHMe2), 1.06 (d, 6, CHMe2), 0.94 (d, 6, CHMe2). 1H NMR (C6D6, 200 MHz) δ 7.48 (mn, 4, Ar), 6.60-7.15 (mn, 10, Ar), 6.92 (m, 1, Ar), 6.59 (t, 1, Ar), 6.34 (m, 1, Ar), 6.26 (d, 1, JHP=8, NH), 3.13 (septet, 2, CHMe2), 1.09 (d, 6, CHMe2), 0.97 (d, 6, CHMe2). 31P{1H} NMR (C6D6, 202 MHz) δ-20.11. 31P{1H} NMR (Et2O, 121.5 MHz) δ-19.87. 31P{1H} NMR (CDCl3, 121.5 MHz) δ-20.17. 13C NMR (CDCl3, 75.3 MHz) δ 150.57 (J=17.1), 147.41, 135.35, 135.26, 135.24, 133.93 (JCP=19.6), 130.28, 128.92, 128.47 (JCP=7.5), 127.14, 123.70, 118.71, 117.63, 111.60, 28.18 (CHMe2), 24.40 (CHMe2), 23.03 (CHMe2). Anal. Calcd. for C30H32NP: C, 82.35; H, 7.37; N, 3.20. Found: C, 82.32; H, 7.36; N, 3.28.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.[Li]CCCC.[CH3:16][O:17][C:18](=[O:29])[C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1Br>C1COCC1.[Cl-].[Cl-].[Zn+2].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>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:20]1[C:19]([C:18]([O:17][CH3:16])=[O:29])=[CH:24][C:23]([N+:25]([O-:27])=[O:26])=[CH:22][CH:21]=1
Reactant: COc1cccc(OC)c1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1cc([N+](=O)[O-])ccc1-c1c(OC)cccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A solution of 1,3-dimethoxybenzene (115.2 ml, 0.88 mol) in anhydrous THF (600 ml) was cooled to 0° C. and treated with n-BuLi (382.4 ml, 0.95 mol, 2.5M solution in hexane) dropwise while maintaining the temperature of the reaction mixture between 0° C. and 5° C. The reaction mixture was allowed to warm to room temperature, stirred for 2 hours and recooled to 0° C. Anhydrous ZnCl2 (141.6 g, 1.04 mol) was added as a solid in portions while maintaining the reaction temperature below 5° C. After adding all the ZnCl2, the reaction mixture was allowed to warm to room temperature and stirred for 2 hours (clear solution). The reaction mixture was recooled to 0° C. and methyl-2-bromo-5-nitrobenzoate (208 g, 0.80 mol) was added as a solid in one portion, followed by the addition of dichloro-bis-(triphenylphosphine) palladium(II) (7 g, 9.90 mmol). Additional THF (200 ml) was added and the reaction mixture was allowed to warm to room temperature. Reaction is exothermic with exotherm starting around 20° C. The reaction mixture was stirred while maintaining the reaction temperature below 45° C. until methyl-2-bromo-5-nitrobenzoate was less than 0.1% peak area detected by HPLC. Solid product started precipitating out typically after 30 minutes. Isopropyl acetate (400 ml) was added and the reaction mixture was stirred for another 30 minutes. The solid was filtered and washed with isopropyl acetate (300 ml), dried at 40° C. under reduced pressure to provide the title compound (203 g, 80%). mp 157° C.; Anal. Calcd. for C16H15NO6: C, 60.57; H, 4.77; N, 4.41; Found C, 60.30; H, 4.76; N, 4.34. 1H NMR [(CD3)2SO] δ 3.65 (3H, s); 3.66 (6H, s), 6.73 (1H, s), 6.77 (1H, s), 7.36 (1H, m), 7.59 (1H, d), 8.36 (1H, dd) and 8.52 (1H, d); 13C [(CD3)2SO] δ 52.1, 104.2, 115.7, 123.7, 125.3, 130.1, 133.0, 134.4, 141.4, 146.0, 156.2, 165.6. The 13C signal for two methoxy groups at 55.6 are overlapping; IR (KBr): 1740 and 1600 cm−1; MS (APCI) m/z: 318 (M+H)+, m/z 335 (M+NH4)+, 340 (M+Na)+; FAB-HRMS: found, 318.0989, required 318.0978.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:23]=[CH:22][C:21]4[O:20][CH2:19][O:18][C:17]=4[CH:16]=3)[N:10]=[C:9]([S:24][CH2:25][C:26]#[N:27])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:29][OH:30].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[O:20]1[C:21]2[CH:22]=[CH:23][C:15]([CH2:14][NH:13][C:11]3[CH:12]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=[C:9]([S:24][CH2:25][C:26](=[N:29][OH:30])[NH2:27])[N:10]=3)=[CH:16][C:17]=2[O:18][CH2:19]1
Reactant: N#CCSc1nc(NCc2ccc3c(c2)OCO3)cc(-c2ccccc2)n1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(CSc1nc(NCc2ccc3c(c2)OCO3)cc(-c2ccccc2)n1)=NO
Reaction time: 8 h

Procedure:
A mixture of 11.20 g. (0.03 mole) of [4-phenyl-6-(piperonylamino)-2-pyrimidinylthio]acetonitrile, 4.14 g. (0.06 mole) of hydroxylamine hydrochloride and 12.70 g. (0.12 mole) of sodium carbonate in 200 ml of N,N-dimethylformamide was heated on a steam bath for four hours. The mixture was filtered and the filtrate was evaporated in a rotary evaporator. The residue was dissolved in ethyl acetate, diluted with petroleum ether and left at room temperature overnight. The precipitate which formed was collected and recrystallized from a mixture of ethyl acetate-petroleum ether to give 4.8 g. of product, mp. 160°-163°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.CO[CH:14](OC)[CH2:15][NH2:16].ClC(OCC)=O.P(OC)(OC)OC.[OH-].[Na+]>C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:7]([CH:14]=[CH:15][N:16]=[CH:5]2)=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COC(CN)OC
Reactant: COc1ccc(C=O)cc1Br
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CCOC(=O)Cl
Agent: COP(OC)OC
Solvent: c1ccccc1
Product: COc1cc2ccncc2cc1Br
Temperature: -10 °C
Reaction time: 8 h
Yield: 26.2 %

Procedure:
3-Bromo-4-methoxybenzaldehyde (10.0 g) was dissolved in benzene (100 ml) to prepare a solution. 2,2-Dimethoxy-ethylamine (4.89 g) was added to the solution, and the mixture was heated under reflux overnight. The solvent was removed by distillation under the reduced pressure, and the residue was then dissolved in tetrahydrofuran (100 ml) to prepare a solution which was then cooled to −10° C. Ethyl chloroformate (5.05 g) and trimethyl phosphite (6.92 g) were added thereto, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, the residue was then dissolved in dichloromethane (100 ml) to prepare a solution. Titanium tetrachloride (53.0 g) was added to the solution, and the mixture was heated under reflux for 36 hr. The reaction solution was cooled to room temperature, was then neutralized with a 1 N aqueous sodium hydroxide solution, and was extracted with 3 N hydrochloric acid. The aqueous layer was made basic with a 3 N aqueous sodium hydroxide solution, was then extracted with dichloromethane, and the solvent was removed by distillation under the reduced pressure to give 7-bromo-6-methoxyisoquinoline (2.90 g, yield 26%).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1Br.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1cc(Br)c(C)s1
Reactant: Nc1ccccc1
Product: COC(=O)c1cc(Nc2ccccc2)c(C)s1
Yield: 15.7 %

Procedure:
A stirred suspension of 400 mg (1.7 mmol) methyl 5-methyl-4-bromo-thiophene-2-carboxylate and 192 μL (2.1 mmol, 1.25 eq) of aniline (Aldrich, Milwaukee, Wis.) was treated in a manner similar to Example 241, step (b) to give 66 mg of the title compound (16%) as a brown glass. 1H-NMR (DMSO-d6, 400 MHz) δ7.70 (s, 1H), 7.56 (s, 1H), 7.17 (m, 2H), 6.72 (m, 3H), 3.79 (s, 3H), 2.31 (s, 3H). Mass spectrum (MALDI, gentisic acid matrix, m/z): Calcd. for C13H13NO2S, 248.1 (M+H), found 247.5.