Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:4]([CH2:16][CH2:17][CH3:18])[C:5]([NH:7][C@@H:8]([CH2:13][CH:14]=[CH2:15])[C:9]([O:11][CH3:12])=[O:10])=[O:6])[CH2:2][CH3:3].I[CH3:20].[H-].[Na+]>C1COCC1>[CH3:20][N:7]([C@@H:8]([CH2:13][CH:14]=[CH2:15])[C:9]([O:11][CH3:12])=[O:10])[C:5](=[O:6])[CH:4]([CH2:1][CH2:2][CH3:3])[CH2:16][CH2:17][CH3:18]
Reactant: CI
Reactant: C=CC[C@H](NC(=O)C(CCC)CCC)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[C@@H](C(=O)OC)N(C)C(=O)C(CCC)CCC
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 25.6 %

Procedure:
Step A (2): (S)-Methyl 2-(2-propylpentanamido)pent-4-enoate (852 mg, 3.34 mmol) from Step A (1) was dissolved in THF (20 mL). Iodomethane (620 μL, 10 mmol) was added and resulting mixture chilled to 0° C. Sodium hydride (120 mg, 5.00 mmol) was added and the ice-bath was removed. After 75 min, the reaction was chilled again to 0° C. and quenched with aqueous 1 N HCl. The slurry was poured into H2O, and extracted with EtOAc (3×200 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography to give (S)-methyl 2-(N-methyl-2-propylpentanamido)pent-4-enoate 230 mg (26% yield). LC-MS (M+H)+=270.22. 1H NMR (300 MHz, CDCl3) δ 0.78-0.90 (m, 5H) 1.10-1.41 (m, 6H) 1.49-1.69 (m, 3H) 2.36-2.50 (m, 1H) 2.60-2.79 (m, 2H) 2.92 (s, 3H) 3.67 (s, 3H) 4.96-5.12 (m, 2H) 5.29 (dd, J=10.98, 4.76 Hz, 1H) 5.58-5.77 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([NH:13][C:14]2[N:15]=[CH:16][C:17]3[CH2:18][C:19](=O)[NH:20][C:21]4[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:22]=4[C:23]=3[N:24]=2)[C:9]([CH3:12])=[N:10][CH:11]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:36].N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([NH:13][C:14]2[N:15]=[CH:16][C:17]3[CH2:18][C:19](=[S:36])[NH:20][C:21]4[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:22]=4[C:23]=3[N:24]=2)[C:9]([CH3:12])=[N:10][CH:11]=1
Reactant: Cc1ncc(CCCN(C)C)cc1Nc1ncc2c(n1)-c1ccc(C(F)(F)F)cc1NC(=O)C2
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: Cc1ncc(CCCN(C)C)cc1Nc1ncc2c(n1)-c1ccc(C(F)(F)F)cc1NC(=S)C2
Temperature: 50 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
A mixture of 2-({5-[3-(dimethylamino)propyl]-2-methylpyridin-3-yl}amino)-9-(trifluoromethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (175 g, 372 mmol), phosphorus pentasulfide (82.7 g, 372 mmol) and pyridine (1.35 L) was heated at 50° C. for 18 hours. HPLC analysis showed completion of the reaction. After the reaction mixture was cooled below room temperature, a solution of sodium carbonate (525 g, 4.95 mol) in 5.1 L of water was slowly added while the temperature was kept at below room temperature. The resulting biphasic solution was separated and the organic layer was washed with the same amount of sodium carbonate solution two times. The organic phase was then reduced to ca. 1.1 L in volume. The solution was diluted with water (1.0 L) and stirred at room temperature overnight resulting in a yellow suspension. The solid was filtered and washed with 200 mL EtOH/water (1 vol/2 vol), and water 200 mL. After drying overnight under vacuo at 40° C., the crude product was dissolved in 1.2 L of EtOH at reflux. Water (2.0 L) was slowly added at 75° C. to induce crystallization. The suspension was then slowly cooled to room temperature and stirred overnight. The solid 2-({5-[3-(Dimethylamino)propyl]-2-methylpyridin-3-yl}amino)-9-(trifluoromethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepine-6-thione was filtered and dried under vac at 40° C. to a constant weight (140.0 g, HPLC purity>98%, 77% yield). LCMS (FA): Rt=6.26 min, m/z=485.2 (M−H).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:20])[C:5]([CH3:19])=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(#N)C>[Cl:1][C:2]1[C:3]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[C:4]([F:20])[C:5]([CH3:19])=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18]
Reactant: C1CNCCN1
Reactant: Cc1c(F)c(F)c(Cl)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CC#N
Product: Cc1c(F)c(N2CCNCC2)c(Cl)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
A suspension of 0.38 g (1.21 mmol) of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.42 g (4.88 mmol) of piperazine and 20 mL of acetonitrile was refluxed for 4 hours, and then stirred at room temperature overnight. The precipitate was collected by filtration, washed with water and acetonitrile, and dried in vacuo to give 0.32 g of the title compound, mp 234°-235° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].C1C([N+]([O-])=O)=CC=C([O:16][P:17](O)([OH:19])=[O:18])C=1.C(O)C>C(OC)(C)(C)C>[P:17]([O:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4])([OH:19])([OH:18])=[O:16]
Reactant: OCC(O)CO
Reactant: O=[N+]([O-])c1ccc(OP(=O)(O)O)cc1
Solvent: COC(C)(C)C
Solvent: CCO
Product: O=P(O)(O)OCC(O)CO
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
Glycerol (10 mmol; 0.92 g) is adsorbed to an approximately equal amount of silica gel (1.0 g) and then suspended in 20 ml of t-BuOMe. To this mixture is added p-nitrophenylphosphate (10 mmol) followed by acid phosphatase from potato (1000 U; 200 mg). The mixture is stirred at room temperature for 24 hours. The solvent is removed by vacuum, the residue is thoroughly extracted with water (3×150 ml), and all solids are removed by filtration. The resulting aqueous solution is concentrated under vacuum to 75 ml and treated with a solution 21 mmol of BaCl2.2H2O to form a precipitate. To the suspension is added 500 ml of 95% ethanol and the precipitate is allowed to settle overnight. The. suspension is filtered and the solid material is dried over CaSO4. Glycerol-1-phosphate (8.5 mmol) is obtained containing 94% of the title compound as the barium salt.
Reaction SMILES: [N:1]([C:38]([CH2:40][O:41][CH2:42][C:43]([OH:45])=O)=[O:39])([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[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][CH3:19].Cl.CN(C)CCCN=C=NCC.[NH2:58][CH2:59][C:60]([O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)=[O:61].CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CCN(CC)CC>[N:1]([C:38]([CH2:40][O:41][CH2:42][C:43]([NH:58][CH2:59][C:60]([O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)=[O:61])=[O:45])=[O:39])([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][CH3:19])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: NCC(=O)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)COCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)COCC(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of (C18H37)2NCOCH2OCH2COOH (1.0 g, 1.5 mmol) in CH2Cl2 (30 mL) was added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (0.31 g, 1.6 mmol) and the reaction was stirred at room temperature. After 0.5 h, Gly-OCH2Ph.TsOH (0.53 g, 1.5 mmol) and Et3N (0.6 mL) were added and the mixture was stirred overnight. The reaction mixture was washed with water (20 mL), 0.5 M aqueous HCl (20 mL), water (20 mL), 10% aqueous Na2CO3 (20 mL), and brine (20 mL) then dried over MgSO4, evaporated and the residue crystallized from MeOH yielding (C18H37)2NCOCH2OCH2CO-Gly-OCH2Ph as a deliquescent white solid (0.86 g, 70%), mp 38–40° C. 1H-NMR (300 MHz, δ, CDCl3) 0.86 (6H, t, J=6.9 Hz), 1.24 (64H, m), 1.50 (4H, bs), 3.06 (2H, t, J=7.5 Hz), 3.28 (2H, t, J=7.5 Hz), 4.10 (2H, s), 4.12 (2H, s), 4.25 (2H, s), 5.15 (2H, s), 7.33 (5H, m), 8.20 (1H, t, J=5.7 Hz). 13C-NMR (75 MHz, 6, CDCl3): 14.2, 22.7, 26.9, 27.1, 27.6, 29.0, 29.39, 29.44, 29.5, 29.6, 29.7, 29.8, 32.0, 40.8, 46.3, 47.0, 67.1, 69.7, 71.8, 128.5, 128.6, 128.8, 135.3, 168.5, 169.8, 170.6.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:4]1[C@@H:7]([C@@H:8]([CH3:27])[C:9]([C:11]2[S:15][C:14]3=[C:16]([C:19]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)=[O:20])[N:17]=[CH:18][N:13]3[CH:12]=2)=O)[N:6]([C:28]([C:48]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=2)=[O:49])=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:5]1=[O:61])[CH3:3]>C1(C)C=CC=CC=1>[OH:1][C@@H:2]([C@H:4]1[C:5](=[O:61])[N:6]2[C:28]([C:48]([O:50][CH2:51][C:52]3[CH:53]=[CH:54][C:55]([N+:58]([O-:60])=[O:59])=[CH:56][CH:57]=3)=[O:49])=[C:9]([C:11]3[S:15][C:14]4=[C:16]([C:19]([C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[O:20])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:8]([CH3:27])[C@H:7]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1[C@@H](C)C(=O)c1cn2cnc(C(=O)c3cccnc3)c2s1
Solvent: Cc1ccccc1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cccnc5)c4s3)[C@H](C)[C@H]12
Yield: 73.2 %

Procedure:
A solution of 46.9 mg of (3S,4R)-3-[(1R)-1-hydroxyethyl]-4-{(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}-1-[4-nitrobenzyloxycarbonyl(triphenylphosphoranylidene)-methyl]azetidin-2-one in 1 ml of toluene was heated under reflux for 3 hr. The solvent was removed by evaporation, and the residue was purified by thin layer chromatography (developed with 10% methanol/methylene chloride) to give 23.1 mg of (4-nitrobenzyl) (1S,5R,6S)-6-[(1R)-1-hydroxyethyl]-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-methylcarbapen-2-em-3-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13])([CH3:4])([CH3:3])[CH3:2].Br[CH2:16][C:17]1[CH:18]=[C:19]([C:22]#[N:23])[S:20][CH:21]=1.[H-].[Na+]>C1COCC1.CN(C=O)C>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([CH2:16][C:17]2[CH:18]=[C:19]([C:22]#[N:23])[S:20][CH:21]=2)[C:9]1=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Reactant: N#Cc1cc(CBr)cs1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(Cc2csc(C#N)c2)C1=O
Reaction time: 2 h
Yield: 86.3 %

Procedure:
To a solution of (2-oxopyrrolidin-3-(S)-yl)carbamic acid tert-butyl ester (3.2 g, 16 mmol) in 80 mL of THF:DMF (10:1) at 0° C. is added 4-bromomethylthiophene-2-carbonitrile (3.23 g, 16 mmol) and sodium hydride (60%) (0.67 g, 16.8 mmol). After addition, the solution is allowed to warm to ambient temperatures. After 2 hours, the solution is quenched by the addition of sat NH4Cl. The solution is diluted with H2O and EtOAc. The layers are separated. The organic layer is washed with H2O and sat. NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with gradient of 20% EtOAc/CH2Cl2 to 30% EtOAc/CH2Cl2 to afford the title compound (4 g, 13.8 mmol) as a white solid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([SH:12])[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=O.[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)#[N:16]>N1C=CC=CC=1>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]1[S:12][C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:14])[F:13])[CH:11]=[CH:10][C:6]=2[C:7](=[O:9])[N:16]=1
Reactant: N#Cc1ccccn1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1S
Solvent: c1ccncc1
Product: O=c1nc(-c2ccccn2)sc2cc(C(F)(F)F)ccc12
Yield: 56 %

Procedure:
A mixture of 4-trifluoromethylthiosalicylic acid (2.5 g, 11 mmol), 2-cyanopyridine (1.2 g, 11 mmol) and pyridine (10 ml) was refluxed for 10 hrs. After cooling, the precipitated crystals were collected by filtration and recrystallized from tetrahydrofuran-hexane to give the titled compound (1.9 g, 54%).
Reaction SMILES: [F:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[N:14]3[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]3)=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7](=[O:20])[C:6]=2[CH:21]=1.[H][H]>FC(F)(F)C(O)=O.[Pd]>[F:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[N:14]3[C:9]([CH2:10][CH2:11][CH2:12][CH2:13]3)=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7](=[O:20])[C:6]=2[CH:21]=1
Reactant: CCOC(=O)c1c(=O)c2cc(F)c(F)cc2n2ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c2n(c3cc(F)c(F)cc3c1=O)CCCC2
Yield: 88.8 %

Procedure:
A mixture of 0.5 g of ethyl 8,9-difluoro-6-oxo-6H-benzo[c]quinolizine-5-carboxylate and 0.5 g of 10% palladium-on-carbon in 50 ml of trifluoroacetic acid was shaken under 40 lb. of hydrogen in a Parr apparatus for 2 hours. The mixture was filtered and the solvent evaporated. The concentrate was partitioned between aqueous sodium bicarbonate and dichloromethane. The organic layer was dried followed by adding hexanes to give 0.45 g of the desired product, mp 166°-168° c.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:15][CH2:14][C:9]2([O:13]CCO2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C([N-]C(C)C)(C)C.[Li+].Br[CH2:25][CH2:26][O:27][CH3:28].Cl>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([CH2:25][CH2:26][O:27][CH3:28])[CH2:7][CH2:8][C:9](=[O:13])[CH2:14][CH2:15]1)=[O:5])[CH3:2]
Reactant: COCCBr
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CCOC)CCC(=O)CC1
Temperature: -5 °C
Reaction time: 2.5 h

Procedure:
A solution of 1,4-dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester (39.5 g) in THF (200 ml) was added dropwise over a period of 45 minutes at −5° C. (ice/methanol bath) to a solution of lithiumdiisopropylamide (2M in THF, 184.3 mL) in THF (300 ml). Stirring was continued for 2.5 hours at 0° C. The reaction mixture was cooled to −5° C. and 2-bromoethyl-methylether (34.6 ml) was added dropwise over a period of 30 minutes. Stirring was continued for 12 hours at RT. The reaction mixture was cooled to 0° C. and aqueous HCl (25%, 300 ml) was added dropwise over a period of 45 minutes to pH 1. Stirring was continued for 2 hours at RT. The reaction mixture was poured into ice/water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a yellow liquid (25.2 g). MS (EI)=288.0 [M+].
Reaction SMILES: CC(C)([O-])C.[K+].Br.[CH3:8][N:9]1[CH2:14][CH2:13][C:12](=[C:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH:19]([Br:26])[CH:18](Br)[C:17]3[CH:28]=[CH:29][CH:30]=[CH:31][C:16]2=3)[CH2:11][CH2:10]1>C(O)(C)(C)C>[CH3:8][N:9]1[CH2:14][CH2:13][C:12](=[C:15]2[C:16]3[CH:31]=[CH:30][CH:29]=[CH:28][C:17]=3[CH:18]=[C:19]([Br:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]2=3)[CH2:11][CH2:10]1
Reactant: CN1CCC(=C2c3ccccc3C(Br)C(Br)c3ccccc32)CC1
Agent: Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CN1CCC(=C2c3ccccc3C=C(Br)c3ccccc32)CC1

Procedure:
To 600 ml. of a 0.40 M (0.24 mole) solution of potassium t-butoxide in t-butanol is added 42.1 g. (0.079 mole) of 1-methyl-4-(10,11-dibromo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-piperidine hydrobromide and the mixture stirred vigorously under anhydrous conditions for 6 hours at room temperature. The reaction mixture is poured into 2 l. of water and extracted 3 times with 100 ml. each of benzene. The combined benzene extracts are dried over anhydrous MgSO4, filtered, the MgSO4 washed with benzene, and the benzene solution evaporated to dryness on a rotary evaporator. There remains 27.9 g. of crystalline product. This product is recrystallized by dissolving in 750 ml. of boiling hexane, filtered hot, the volume reduced to 200 ml. by boiling off hexane, seeding and allowing to crystallize. The crystals are collected and dried in a vacuum oven at 60°C. overnight to give 1-methyl-4-(10-bromo-5H-dibenzo[a,d]cyclohepten-5-ylidene)-piperidine, m.p. 127°-129°C. Three more recrystallizations from hexane given an analytical sample with m.p. 130°-131°C.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][N:7]2[C:12]=1[C:11](=O)[NH:10][CH:9]=[N:8]2)([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:11]1[C:12]2=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=[CH:6][N:7]2[N:8]=[CH:9][N:10]=1
Reactant: CC(C)c1ccn2nc[nH]c(=O)c12
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)c1ccn2ncnc(Cl)c12
Temperature: 25 °C

Procedure:
5-Isopropylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (0.035 g, 0.198 mmol, 1.0 equiv) was added to phosphorous oxychloride (2.0 ml, 21.5 mmol, 109 equiv) under a nitrogen atmosphere. The reaction mixture was heated to reflux for 1.5 h. The mixture was cooled to room temperature then concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was extracted twice with ethyl acetate. The combined organic washes were dried over anhydrous magnesium sulfate and concentrated in vacuo to yield a tan solid that was used in the next step without further purification. MS(ESI+) m/z 196 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH2:19][NH2:20].C(O)(=O)C>O>[NH:19]([C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1)[NH2:20]
Reactant: NN
Reactant: CC(C)Cn1cnc2c(Cl)nc3ccccc3c21
Solvent: CC(=O)O
Solvent: O
Product: CC(C)Cn1cnc2c(NN)nc3ccccc3c21

Procedure:
4-Chloro-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (10.0 g, 0.0385 moles, U.S. Pat. No. 4,689,338 Example 77) was added to hydrazine (30 mL). The mixture heated rapidly to reflux. The solid dissolved with a vigorous heat of reaction then a precipitate formed as the reaction mixture refluxed. The reaction mixture was diluted with water. The precipitate was isolated by filtration then suspended in water (100 mL). The solid was brought into solution by the addition of acetic acid. The solution was filtered to remove traces of undissolved solid. The filtrate was made basic by the addition of ammonium hydroxide. The resulting precipitate was isolated by filtration, washed with water then dried to provide 8.0 g of crude product as a white solid. A sample of this material was recrystallized from methanol to provide 4-hydrazino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline, m.p. 202°-205° C. Analysis: Calculated for C14H17 N5 : % C, 65.86; % H, 6.71; % N, 27.43; Found: % C, 65.20; % H, 6.6; % N, 27.5.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1.[C:15]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].O>C1COCC1>[NH2:9][C:8]1[CH:10]=[CH:11][C:5]([O:4][CH2:3][CH2:2][N:25]2[CH2:24][CH2:23][N:22]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:27][CH2:26]2)=[CH:6][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Nc1ccc(OCCBr)cc1[N+](=O)[O-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CCOc2ccc(N)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.9 %

Procedure:
A 100 mL flask was charged with 4-(2-bromoethoxy)-2-nitroaniline (2.2 g, 8.4 mmol) in THF (20 mL) and 4-N-boc-piperazine (1.56 g, 8.4 mmol) was added and stirred at room temperature. The reaction was monitored by LCMS. After 30 minutes, the reaction mixture was treated with deionized water (100 mL) and sonicated. The resulting solid was collected by filtration and dried at reduced pressure to give 1.75 g of tert-butyl 4-(2-(4-amino-3-nitrophenoxy)ethyl)piperazine-1-carboxylate (59% yield). MS (EI): 367 (MH+).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:3]=1.[CH3:20][Si:21]([C:24]#[C:25][Sn](CCCC)(CCCC)CCCC)([CH3:23])[CH3:22]>>[OH:19][C:16]1[CH:17]=[CH:18][C:13]([C:4]2[CH:3]=[C:2]([C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=3)[N:5]=2)=[CH:14][CH:15]=1
Reactant: Oc1ccc(-c2cc(Br)c3cc(O)ccc3n2)cc1
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Product: C[Si](C)(C)C#Cc1cc(-c2ccc(O)cc2)nc2ccc(O)cc12
Yield: 83 %

Procedure:
This compound was prepared from 6a and (trimethylsilylethynyl)tributyltin according to method J. Yellow powder; Yield: 83%; mp 210° C. (dec.); 1H-NMR (300 MHz, acetone-d6) δ 0.38 (s, 9H), 7.02 (d, J=8.7 Hz, 2H), 7.44 (dd, J=9.1, 2.7 Hz, 1H), 7.63 (d, J=2.7 Hz, 1H), 7.99 (d, J=9.1 Hz, 1H), 8.05 (s, 1H), 8.18 (d, J=8.7 Hz, 2H), 8.70 (s, 1H), 9.15 (s, 1H); MS (ESI) m/z 332 ([M−H]−), 334 ([M+H]+); Anal. Calcd for C20H19NO2Si: C: 72.04, H: 5.74, N: 4.20. Found: C: 71.67, H: 5.79, N: 4.07.
Reaction SMILES: [NH:1]1[CH2:5][C:4](=[O:6])[NH:3][CH2:2]1.[F:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][C:13]=1F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][C:13]=1[N:1]1[CH2:5][C:4](=[O:6])[NH:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: O=C1CNCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1CN(c2ccc([N+](=O)[O-])cc2F)CN1
Temperature: 25 °C
Yield: 78.4 %

Procedure:
A solution of 4-imidazolidinone (9.5 g, 110.5 mmol), 3,4-difluoro nitrobenzene (12.2 ml, 110.5 mmol) and diisopropyl ethylamine (28.6 ml, 165 mmol) in dry DMF (80 ml) was heated to 60° C. overnight under argon. The reaction mixture was allowed to cool to room temperature and ice pieces were added. The solid formed was filtered and washed with water. The solid was dried under air to yield the nitro compound (19.5 g, 78.5%) as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH:10]1([C:14]#[N:15])[CH2:13][CH2:12][CH2:11]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:10]2([C:14]#[N:15])[CH2:13][CH2:12][CH2:11]2)[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: N#CC1CCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC1(c2cc(Cl)nc(Cl)n2)CCC1
Reaction time: 3 h
Yield: 11.8 %

Procedure:
To a stirring solution of 2,4,6-trichloropyrimidine (1.00 g, 5.45 mmol) and cyclobutanecarbonitrile (0.53 mL, 5.5 mmol) in anhydrous THF (27 mL) at −78° C. and under nitrogen was added lithium bis(trimethylsilyl)amide (6.0 mL, 6.0 mmol, 1.0 M solution in THF) over 3 min. The cooling bath was removed after 5 further min, and stirring continued for 3 h. The reaction was quenched by the addition of sat. aq. NH4Cl, extracted with CH2Cl2 and organics dried over MgSO4. Following concentration, the reaction residue was purified by flash column chromatography (100:0 heptanes/EtOAc-85:15 heptanes/EtOAc) to afford the title compound as a colorless solid (0.147 g, 12%); 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 2.97-2.82 (m, 2H), 2.82-2.67 (m, 2H), 2.51-2.35 (m, 1H), 2.35-2.16 (m, 1H).