Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C=C(C(C)C(C2C=CC(Cl)=CC=2)([NH:13][C:14](=[O:29])[C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=2)([CH3:17])[CH3:16])C)C=C(F)C=1)#N.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[F:28][C:25]([F:26])([F:27])[C:22]1[CH:23]=[CH:24][C:19]([O:18][C:15]([CH3:16])([CH3:17])[C:14]([NH2:13])=[O:29])=[N:20][CH:21]=1
Reactant: CC(c1cc(F)cc(C#N)c1)C(C)(NC(=O)C(C)(C)Oc1ccc(C(F)(F)F)cn1)c1ccc(Cl)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Product: CC(C)(Oc1ccc(C(F)(F)F)cn1)C(N)=O

Procedure:
N-[2-(3-Cyano-5-fluorophenyl)-4-hydroxyphenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide was prepared from N-[2-(3-cyano-5-fluorophenyl)-(4-chlorophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide (Step A, slower eluting isomer) following the procedure described in Reference Example 8, Step B using tris(dibenzylideneacetone) dipalladium and tri(tert-butyl)phosphine as the catalyst. 1H NMR (500 MHz, CD3OD): δ 8.27 (d, 1H), 7.96 (br s, 1H), 7.94 (d, 1H), 7.93 (d, 1H), 7.30 (m, 1H), 7.18 (br s, 1H), 7.14 (m, 1H), 7.04 (d, 1H), 6.65 (ABq, 4H), 4.24 (m, 1H), 3.03 (dd, 1H), 2.88 (m, 1H), 2.57 (dd, 1H), 1.75 (s, 3H), 1.73 (s, 3H), 0.82 (d, 3H). LC-MS: m/e 530 (M+H)+ (3.8 min).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[Cl:9].[OH-].[K+].[C:12]([OH:16])(=[O:15])[CH2:13][SH:14].ClCC([O-])=O.[Na+]>CN1CCCC1=O>[Cl:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[CH:13]([SH:14])[C:12]([OH:16])=[O:15]
Reactant: O=C(O)CS
Reactant: Clc1ccc(Cl)c(Br)c1
Agent: O=C([O-])CCl
Agent: [K+]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C(O)C(S)c1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
Using the same procedure as in Example 8, 45.2 g (0.2 mol) of 1-bromo-2,5-dichlorobenzene, 23.7 g (0.4 mol) of 95% potassium hydroxide, 18.4 g (0.2 mol) of thioglycolic acid and 320 g of N-methyl-2-pyrrolidone were added, followed by stirring at 140° to 150° C. for 2 hours. Then, 30.4 g (0.26 mol) of sodium monochloroacetate was added to the reaction solution, followed by stirring at 90° C. for 1 hour. After distilling off the solvent, 300 g of water and 50 g of toluene were added for layer separation. To the water layer was added 45 g of concentrated hydrochloric acid, and the mixture was cooled to room temperature. The resulting crystal was filtered and dried to yield 34.0 g of 2,5-dichlorophenylthioglycolic acid with a yield of 71.7%. The results are given in Table 2.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(N1CCC2C(=C(OS(C(F)(F)F)(=O)=O)N(C3C=CC=CC=3)N=2)CC1)=O)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+].S1C=CC=C1B(O)O>CN(C=O)C.O>[C:18]1([N:13]2[C:12]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(-c3ccccc3)c(-c3cccs3)c2CC1
Agent: CC(C)(C)OC(=O)N1CCc2nn(-c3ccccc3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Agent: O=C([O-])[O-]
Agent: OB(O)c1cccs1
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(-n2nc3c(c2-c2cccs2)CCNCC3)cc1
Temperature: 80 °C

Procedure:
2-Phenyl-3-thiophen-2-yl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester. To a solution of 199.8 mg of 2-phenyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 176, Step B) in 3.5 mL of DMF were added 0.6 mL of 2 M aq. Na2CO3 and 75.6 mg of thiophene-2-boronic acid. PdCl2dppf (20.2 mg) was added and the mixture was heated at 80° C. for 16 h. The mixture was poured into water (50 mL) and extracted with CH2Cl2 (3×15 mL) and the combined organic layers were concentrated in vacuo. Chromatography on SiO2 (0 to 50% EtOAc/hexanes) afforded 58.9 mg of the desired compound as a white solid. MS (ESI): exact mass calculated for C22H25N3O2S, 395.17; found, m/z 396.1 [M+H]+.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][C:14]1([CH3:23])[O:21][CH2:20][CH2:19][CH:18]2[N:15]1[C:16](=[O:22])[CH2:17]2.[N-:24]=[N+:25]=[N-:26].C[Si](Cl)(C)C>CCCCCC.O1CCCC1>[CH3:13][C:14]1([CH3:23])[O:21][CH2:20][CH2:19][CH:18]2[N:15]1[C:16](=[O:22])[CH:17]2[N:24]=[N+:25]=[N-:26]
Reactant: CC1(C)OCCC2CC(=O)N21
Reactant: [N-]=[N+]=[N-]
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1(C)OCCC2C(N=[N+]=[N-])C(=O)N21

Procedure:
In a nitrogen stream under stirring, 50 ml of dry tetrahydrofuran is cooled to -78° C. and, then, 20 ml of a solution of 15% n-butyllithium in n-hexane is added thereto. After dropwise addition of 3.66 ml of diisopropylamine, the mixture is stirred at -78° C. for 15 minutes. A solution of 3.1 g of 2,2-dimethyl-1-aza-3-oxabicyclo[4.2.0]octan-8-one in 15 ml of dry tetrahydrofuran is added dropwise and the mixture is stirred at -78° C. for one hour. Then, a solution of 4.34 g of p-toluenesolfonyl azide in 15 ml of dry tetrahydrofuran is added dropwise and the mixture is stirred at -50° C. to -60° C. for 1.5 hours. To this mixture 5.1 ml of trimethylsilyl chloride is added dropwise and the reaction mixture is heated under reflux for 5 hours. Ater cooling, the insolubles are filtered off and the filtrate is concentrated under reduced pressure. The residue is shaken with water and ethyl acetate and the ethyl acetate layer is separated, washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The solvent is then distilled off and the residue is purified by silica gel column chromatography to give 2,2-dimethyl-7-azido-1-aza-3-oxabicyclo[4.2.0]-octan-8-one as a 1:4 mixture of cis- and trans-isomers.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9](O)(=[O:13])[C:10]([CH3:12])=O>>[CH3:12][C:10]1[C:9](=[O:13])[NH:7][C:2]2[C:1]([N:8]=1)=[CH:6][CH:5]=[CH:4][CH:3]=2
Reactant: Nc1ccccc1N
Reactant: CC(=O)C(=O)O
Product: Cc1nc2ccccc2[nH]c1=O

Procedure:
Reaction between 1,2-phenylene-diamine and pyruvic acid gave after recrystallisation (EtOH) the title compound as a beige solid;
Reaction SMILES: [CH:1]1[C:6]([CH2:7][CH2:8][OH:9])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.N1C=CC=CC=1.ClC(Cl)([O:20][C:21](=[O:27])[O:22]C(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH:1]1[C:6]([CH2:7][CH2:8][OH:9])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.[C:21](=[O:20])([O-:27])[O-:22]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: OCCc1ccc(O)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C([O-])[O-]
Reaction time: 0.25 h

Procedure:
In a 1 L 3-necked round-bottomed flask equipped with a mechanical stirrer, and a liquid addition device were placed 45 g (0.084 mol) of I2DTy, 5 g (0.036 mol) of tyrosol, 35.5 g (0.45 mol) of pyridine, and 300 mL of DCM and stirred for 15 min to get a clear solution. Triphosgene (12.3 g, 0.125 mol of phosgene) was dissolved in 32 ml of DCM and the solution was introduced into the reaction flask over 2-3 hours. After the addition was complete, the reaction mixture was quenched with a mixture of 135 mL of THF and 15 mL of water. 350 mL of water was added to the reaction mixture and stirred for 5 min. After allowing the layers to separate, the top aqueous layer was removed and discarded. The washing, was repeated with two additional 350 mL portions of DI water. The reaction mixture was then precipitated with 600 mL of IPA. The resulting gel was ground twice in a 4 L high speed blender. The precipitate obtained was isolated by filtration and dried in a vacuum oven at 80° C. The polymer had a Mw of 318 Kda and a glass transition temperature (Tg) of 100° C. 1H NMR spectrum of the polymer was in agreement with the structure. Compression molding at 190° C. gave a uniform transparent film. Using similar procedures a copolymer with 15% tyrosol was prepared. The properties of the polymers are set forth below:
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:12])[CH2:5][CH2:4]1.[Cl:30][Si](C)(C)C.CCOCC>CC(C)=O.CC(=O)CC>[ClH:30].[CH3:29][N:2]([CH3:1])[C:3]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:12])[CH2:5][CH2:4]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccc2)CCC(CNC(=O)NCCCc2ccccc2)CC1
Solvent: CCC(C)=O
Solvent: CCOCC
Solvent: CC(C)=O
Product: Cl
Reaction time: 1 h

Procedure:
In the manner described for Example 27, 255 mg of the polar diastereoisomer of 1-(4-dimethylamino-4-phenylcyclohexylmethyl)-3-(3-phenylpropyl)urea were also obtained (m.p. 159–165° C.). 249 mg (0.63 mmol.) thereof were dissolved in acetone (7 ml) and 2-butanone (15 ml), and chlorotrimethylsilane (121 μl, 0.95 mmol.) was added dropwise at RT, with stirring. After stirring for 1 h, the reaction solution was reduced to about 0.5 ml in vacuo, ether (10 ml) was added thereto, and vigorous stirring was carried out for 1 h at RT. The resulting solid was filtered off with suction, washed with ether (3×2.5 ml) and dried in vacuo. 270 mg of the corresponding hydrochloride of the polar urea were obtained (greyish-white solid, m.p. 100–110° C.).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[CH2:17][CH:16]4[C:18]5([CH2:22][N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[S:20](=[O:29])(=[O:28])[NH:19]5)[CH:13]([CH2:14][CH2:15]4)[CH2:12][C:11]=3[CH:30]=2)=[N:4][CH:3]=1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O>>[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[CH2:17][CH:16]4[C:18]5([CH2:22][N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[S:20](=[O:29])(=[O:28])[NH:19]5)[CH:13]([CH2:14][CH2:15]4)[CH2:12][C:11]=3[CH:30]=2)=[N:4][CH:3]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: O=S1(=O)NC2(CN1CC(F)(F)F)C1CCC2Cc2cc(-c3ncc(Br)s3)ccc2C1
Product: O=S1(=O)NC2(CN1CC(F)(F)F)C1CCC2Cc2cc(-c3ncc(-c4ccccc4C(F)(F)F)s3)ccc2C1

Procedure:
Prepared using the bromide from Example 36 Step 2 and 2-trifluoromethylbenzeneboronic acid by the method described for Example 36 Step 3. MS (ES+) 588 ([MH]+).
Reaction SMILES: N[S:2]([C:5]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([CH:20]([CH3:22])[CH3:21])[C:6]=1[C:7]([N:9](CC)CC)=[O:8])(=[O:4])=[O:3]>C(O)(=O)C>[CH:20]([C:14]1[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=[C:5]2[C:6]=1[C:7](=[O:8])[NH:9][S:2]2(=[O:4])=[O:3])([CH3:22])[CH3:21]
Reactant: CCN(CC)C(=O)c1c(C(C)C)cc(OC)cc1S(N)(=O)=O
Solvent: CC(=O)O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)NC2=O
Temperature: 25 °C
Yield: 90.7 %

Procedure:
A solution of 2.aminosulfonyl-6-isopropyl-4-methoxy-N,N-diethylbenzamide (429.6 g) in acetic acid (1.5 L) was refluxed for 20 hours, then cooled to room temperature. The solvent was removed under vacuum. The oily residue was dissolved in water (6 L) and the pH was adjusted to 1 with hydrochloric acid (6N). The crude product was collected by filtration, washed with water (2 L), dried at 60° C. under vacuum for 18 hours and recrystallized from ethyl acetate-hexane to give 4-isopropyl-6-methoxysaccharin (303 g, 91% yield, m.p. 188° C.).
Reaction SMILES: Br[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][C:17]([O:19][CH3:20])=[O:18].[NH2:21][C:22]1[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=1.CN(C)P(N(C)C)(N(C)C)=O>O>[C:17]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:31][CH:32]=1)([O:19][CH3:20])=[O:18]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COC(=O)CCCCCCCCCCCCCCCBr
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)c1ccc(NCCCCCCCCCCCCCCCC(=O)OC)cc1

Procedure:
A solution of 21 g. of methyl 16-bromohexadecanoate and 20 g. of ethyl 4-aminobenzoate in 150 ml. of hexamethylphosphoramide is stirred at 120° C. for 20 horus, cooled, diluted with water and filtered. A methylene chloride solution of the solid is dried over anhydrous magnesium sulfate, clarified with activated charcoal, and filtered through silica gel. The filtrate is evaporated and the residue crystallized from acetonitrile to yield ethyl 4-(15-carbomethoxypentadecylamino)benzoate as a white crystalline solid.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:36][CH:37]([F:39])[F:38])=[C:13]([C:15]2[C:19]([NH:20][C:21]([C:23]3[CH:24]=[N:25][N:26]4[CH:31]=[CH:30][CH:29]=[N:28][C:27]=34)=[O:22])=[CH:18][N:17]([CH2:32][C:33](O)=[O:34])[N:16]=2)[CH:14]=1.Cl.[N:41]1([CH:47]2[CH2:52][CH2:51][O:50][C:49](=[O:53])[CH2:48]2)[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:36][CH:37]([F:39])[F:38])=[C:13]([C:15]2[C:19]([NH:20][C:21]([C:23]3[CH:24]=[N:25][N:26]4[CH:31]=[CH:30][CH:29]=[N:28][C:27]=34)=[O:22])=[CH:18][N:17]([CH2:32][C:33](=[O:34])[N:44]3[CH2:43][CH2:42][N:41]([CH:47]4[CH2:52][CH2:51][O:50][C:49](=[O:53])[CH2:48]4)[CH2:46][CH2:45]3)[N:16]=2)[CH:14]=1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Reactant: O=C1CC(N2CCNCC2)CCO1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C1CC(N2CCN(C(=O)Cn3cc(NC(=O)c4cnn5cccnc45)c(-c4cc(Cl)ccc4OC(F)F)n3)CC2)CCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid trifluoroacetate (100 mg, 0.17 mmol) in DMF (3 mL) was added 4-(piperazin-1-yl)oxan-2-one hydrochloride (76 mg, 0.34 mmol), DIEA (67.2 mg, 0.52 mmol), HATU (79.2 mg, 0.21 mmol). The resulting solution was stirred at room temperature overnight and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (35.0% up to 39.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 35.0% in 2 min); Detector, UV 254/220 nm. This resulted in 14.5 mg (13%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-[4-(2-oxooxan-4-yl)piperazin-1-yl]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid. LCMS (Method 28) [M+H]+=629.1, RT=1.44 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.34 (dd, 1H, J=2.0, 7.2 Hz), 8.69-8.68 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.55 (d, 1H, J=2.8 Hz), 7.45 (d, 1H, J=8.8 Hz), 7.28 (dd, 1H, J=4.4, 7.2 Hz), 7.08 (t, 1H, J=73.2 Hz), 5.24 (s, 2H), 4.35-4.29 (m, 1H), 4.19-4.16 (m, 1H), 3.50-3.32 (m, 6H), 3.02-2.99 (m, 1H), 2.69-2.51 (m, 4H), 2.08-1.98 (m, 1H), 1.77-1.75 (m, 1H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]Br.[CH3:9][O-:10].[Na+].CCCCCC.O>CO>[CH3:9][O:10][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1]
Reactant: BrCCCCCCBr
Reactant: C[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CO
Product: COCCCCCCBr
Reaction time: 0.5 h
Yield: 93 %

Procedure:
6-Bromohexyl methyl ether was prepared from 1,6-dibromohexane. To 48.8 g (200 mmol) of 1,6-dibromohexane at 60° C. was added 44 g (200 mmol) of a 25% solution of sodium methoxide in methanol. The reaction mixture was held 0.5 hours, then an additional 4 g of sodium methoxide solution was added, and the reaction mixture was held an additional hour. Hexane and water were added, the organic phase was washed with brine and dried with magnesium sulfate, filtered and stripped. Fractional distillation under vacuum gave 93% pure 6-bromohexyl methyl ether. This bromide was converted to the Grignard reagent, which was converted to 1-(7-methoxyheptyl)-cyclopropene in the same manner that pentylmagnesium bromide was converted to 1-hexylcyclopropene.
Reaction SMILES: [CH3:1][C:2]([NH:13]C(=O)CC1C=CC=CC=1[N+]([O-])=O)([CH3:12])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[H][H]>C(O)(=O)C.[Pd]>[CH3:1][C:2]([CH3:12])([NH2:13])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: [H][H]
Reactant: CC(C)(CCCc1cccnc1)NC(=O)Cc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(N)CCCc1cccnc1
Yield: 77.8 %

Procedure:
A solution of 35.2 g of N-[1.1-dimethyl-4-(3-pyridyl) butyl]-2-nitrobenzeneacetamide in 250 mL of acetic acid was hydrogenated over 3.5 g of 10% Pd/C at atmospheric Pressure and ambient temperature. The reaction was exothermic and stopped abruptly after the uptake of the theoretical amount of hydrogen (7.5 L). The catalyst was removed by filtration and the filtrate was heated at reflux for 90 minutes. After the solution was cooled. 10 mL of conc. HCl was added and the solvent was removed under reduced pressure. The residue was taken up in IL of water and extracted with ethyl acetate (4×200 mL) to remove the by product, oxindole. The aqueous layer was basified with 10N NaOH and extracted with dichloromethane to give. after evaporation of the dried (K2CO3) extracts 15 g of product. The material was distilled on a Kugelrohr apparatus (95° C; 0.1 mm) to yield 14.3 g of alpha,alphadimethyl-3-pyridinebutanamine.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([OH:26])/[CH:21]=[CH:22]/[CH2:23][CH2:24][CH3:25].[CH2:27]([C:32]12[CH2:39][CH2:38][C:35]([C:40]3[CH:45]=[CH:44][C:43](O)=[CH:42][CH:41]=3)([CH2:36][CH2:37]1)[CH2:34][CH2:33]2)[CH2:28][CH2:29][CH2:30][CH3:31].CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH2:20]([O:26][C:43]1[CH:44]=[CH:45][C:40]([C:35]23[CH2:38][CH2:39][C:32]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([CH2:37][CH2:36]2)[CH2:33][CH2:34]3)=[CH:41][CH:42]=1)/[CH:21]=[CH:22]/[CH2:23][CH2:24][CH3:25]
Reactant: CCC/C=C/CO
Reactant: CCCCCC12CCC(c3ccc(O)cc3)(CC1)CC2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC/C=C/COc1ccc(C23CCC(CCCCC)(CC2)CC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triphenylphosphine (0.34 g, 0.0013 mol) was added in small portions to a solution of (E)-hex-2-en-1-ol (0.13 g, 0.0013 mol), 4-(4-pentylbicyclo[2.2.2]octyl)phenol (0.35 g, 0.0013 mol), diethylazodicarboxylate (0.22 g, 0.0013 mol) in dry tetrahydrofuran (20 cm3), cooled in an ice bath under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel using a 9:1 petroleum ether (40-60° C./ethyl acetate mixture as eluent, followed by recrystallisation from ethanol to yield 0.18 g (39%), K 69° C., SA-N 59° C., N-I 134° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].Cl.[CH3:7][N:8]=[C:9]([NH2:18])[NH:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16]Cl)[N:15]=1>Cl>[CH3:7][N:8]=[C:9]([NH2:18])[NH:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][S:5][CH2:4][CH2:3][NH2:2])[N:15]=1
Reactant: NCCS
Reactant: CN=C(N)Nc1nc(CCl)cs1
Agent: Cl
Product: CN=C(N)Nc1nc(CSCCN)cs1
Yield: 82.2 %

Procedure:
Cysteamine hydrochloride (1.89 g; 16.6 mmoles) and 2-(2-methylguanidino)-4-chloromethylthiazole hydrochloride (4.0 g; 16.6 mmoles) [prepared from (N-methylamidino)thiourea and 1,3-dichloro-2-propanone] were combined in 20 ml of concentrated hydrochloric acid and the solution was heated at an oil bath temperature of 100°. After 2 hours the mixture was evaporated under reduced pressure and the residue made basic with 40% aqueous NaOH solution. The aqueous phase was extracted several times with methyl acetate and the organic phase was dried, filtered and evaporated to give 3.35 g of the title compound. The NMR spectrum (60 MHz) in D2O gave the following characteristic resonances δ: 6.52 (s, 1H), 3.60 (s, 2H), 2.70 (m, 7H).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[N:7][CH:6]=1)[NH2:4].[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=O)=[CH:14][CH:13]=1.N>>[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]2[O:1][N:2]=[C:3]([C:5]3[CH:10]=[CH:9][N:8]=[N:7][CH:6]=3)[N:4]=2)=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NC(=NO)c1ccnnc1
Agent: N
Product: Fc1ccc(-c2nc(-c3ccnnc3)no2)cc1

Procedure:
The titled compound was prepared according to the procedure of Method D using the product of Example 83D and 4-fluorobenzoyl chloride (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.36-7.45 (m, 2 H), 8.29-8.40 (m, 3 H), 9.45 (dd, J=5.6, 1.2 Hz, 1 H), 9.86 (dd, J=2.4, 1.2 Hz, 1 H) ppm; MS (DCI/NH3) m/z=243 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=3)=[N:6]2)[CH2:3][CH2:2]1.[N:27]1([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[C:36]([O:35][C:33]([N:27]1[CH2:32][CH2:31][N:30]([CH2:12][C:9]2[C:10](=[O:11])[N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[N:6]=[C:7]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=3)[CH:8]=2)[CH2:29][CH2:28]1)=[O:34])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1F
Product: COc1ccc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(CC3CC3)n2)cc1F
Yield: 98.9 %

Procedure:
Following the procedure of Example 1(10), 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a pale brown oil (yield: 98.9%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[C:21](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:21])[C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reaction time: 4 h
Yield: 94 %

Procedure:
To a solution of 1.4 g (0.0046 mole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-100) in 30 mL of dimethylformamide was added 2.27 g (0.0069 mole) of cesium carbonate, followed by 0.87 mL (0.014 mole) of iodomethane. After stirring four hours, the mixture filtered and then concentrated under reduced pressure. Ice water was added to the residue to give a precipitate. The solid was collected by filtration, washed with water and dried under vacuum to give 1.37 g of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-100) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[OH-].[Na+].C([O-])(=O)C.[Na+].[C:17](=[C:20]([CH2:23][CH2:24]Cl)[CH2:21]Cl)([CH3:19])[CH3:18]>O>[C:17](=[C:20]1[CH2:23][CH2:24][C:6]2([CH:7]=[C:2]([CH3:1])[C:3](=[O:9])[CH:4]=[C:5]2[CH3:8])[CH2:21]1)([CH3:19])[CH3:18]
Reactant: CC(C)=C(CCl)CCCl
Reactant: Cc1ccc(C)c(O)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1=CC2(CCC(=C(C)C)C2)C(C)=CC1=O
Temperature: 15 °C
Reaction time: 6 h
Yield: 106.9 %

Procedure:
2,5-Dimethylphenol (9.7 g, 0.08 mol) was added to a solution of sodium hydroxide (3.2 g, 0.08 mol) and sodium acetate (3.3 g, 0.04 mol) in distilled water (50 mL). The mixture was cooled to 15° C. and 2-isopropylidene-1,4-dichlorobutane (15 g, 0.09 mol) was added over 1 hour under nitrogen. After stirring at room temperature for 6 hours, the reaction mixture was extracted with ether. The ether extracts were washed with 10% sodium hydroxide, water, and dried (Na2SO4). Concentration gave 18.5 g of crude material consisting of mainly the alkylated phenol having the structure: ##STR38## A sample purified by column chromatography (silica gel) had the following spectral characteristics: