Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[N:12][C:13]([CH:16]([NH:18][C:19](=O)[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:17])=[CH:14][N:15]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O>ClCCCl>[CH3:17][C:16]1[N:18]=[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:12]2[C:13]=1[CH:14]=[N:15][C:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[N:11]2
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)Cc3ccccc3)nn2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COc1ccc(Nc2ncc3c(C)nc(Cc4ccccc4)n3n2)cc1
Yield: 52.1 %

Procedure:
Applying the Cyclization Procedure 1, using N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]-2-phenylacetamide (Intermediate 66) (90 mg, 0.25 mmol), 1,2-dichloroethane (5 mL) and phosphorus oxychloride (0.20 mL, 2.14 mmol), to afford 5-methyl-N-[4-(methyloxy)phenyl]-7-(phenylmethyl)imidazo[5,1-f][1,2,4]triazin-2-amine (45 mg) as a yellow solid. MS m/z 346 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C@:15]3([CH3:20])[C:17]([CH3:19])([CH3:18])[C@@H:12]([CH2:13][CH2:14]3)[C:11]=2[C:10](=[O:21])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Br>CN(C)C=O>[CH2:1]([N:8]1[C:16]2[C@:15]3([CH3:20])[C:17]([CH3:18])([CH3:19])[C@@H:12]([CH2:13][CH2:14]3)[C:11]=2[C:10](=[O:21])[N:9]1[CH2:26][C:25]1[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=1[C:23]([F:22])([F:32])[F:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1c2c(=O)[nH]n1Cc1ccccc1
Reactant: FC(F)(F)c1ccccc1CBr
Solvent: CN(C)C=O
Product: CC1(C)[C@H]2CC[C@]1(C)c1c2c(=O)n(Cc2ccccc2C(F)(F)F)n1Cc1ccccc1
Temperature: 110 °C
Yield: 56.4 %

Procedure:
A solution of (4R,7S)-1-benzyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 49; 96 mg, 0.33 mmol) and 2-(trifluoromethyl)benzyl bromide (85 mg, 0.35 mmol) in dimethylformamide (3.4 mL) was heated at 100° C. for 24 h. A second portion of 2-(trifluoromethyl)benzyl bromide (85 mg, 0.35 mmol) was added and the mixture was heated at 110° C. overnight. The solvent was evaporated and dichloromethane (100 mL) was added. The solution was washed with saturated aqueous sodium thiosulfate (150 mL), saturated aqueous sodium hydrogen carbonate (150 mL) and brine (150 mL), dried (sodium sulfate), filtered, evaporated and purified using a Biotage 40S system, eluting with 2% methanol/dichloromethane, to give (4R,7S)-1-benzyl-7,8,8-trimethyl-2-(2-trifluoromethyl-benzyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (82 mg, 55%) as an off-white solid. APCI(+)-MS (M+H) 441.
Reaction SMILES: [C:1]([CH2:4][S:5][C:6]1[C:7]([CH3:15])=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10])([OH:3])=[O:2].S(Cl)(Cl)=O.[Cl-].[Cl-].[Cl-].[Al+3].[CH2:24](Cl)Cl>>[C:1]([CH2:4][S:5][C:6]1[C:7]([CH3:15])=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([O:11][CH3:24])=[O:10])([OH:3])=[O:2]
Reactant: Cc1c(SCC(=O)O)cccc1C(=O)O
Reactant: ClCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(SCC(=O)O)c1C
Temperature: 20 °C
Reaction time: 1 h

Procedure:
14.3 g (0.06 mmol) of 3-carboxymethylthio-2-methylbenzoic acid are dissolved in 300 ml of methylene chloride and 13.1 g (0.11 mmol) of thionyl chloride are added dropwise. The mixture is refluxed for 1 hour and the solvent and excess thionyl chloride are then distilled off. The residue is taken up in 100 ml of methylene chloride and treated with 31.8 g (0.24 mmol) of aluminum trichloride. The reaction is stirred at about 20° C. for 1 hour. The mixture is then added to ice-water and the organic phase is separated off. After washing and drying the organic phase, the solvent is removed. The product is reacted further without purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:10]=[CH:11][N:12](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:13]=2)=[CH:4][CH:3]=1.[Cl:33][C:34]1[N:39]=[C:38]([N:40]2[CH:45]=[CH:44][C:43]([CH2:46]N3C(CC4C=CC(C#N)=CC=4)=CN=C3)=[CH:42][C:41]2=[O:61])[CH:37]=[N:36][CH:35]=1>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[N:10]([CH2:46][C:43]3[CH:44]=[CH:45][N:40]([C:38]4[CH:37]=[N:36][CH:35]=[C:34]([Cl:33])[N:39]=4)[C:41](=[O:61])[CH:42]=3)[CH:11]=[N:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(Oc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reactant: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3cncc(Cl)n3)c(=O)c2)cc1
Solvent: CC#N
Product: O=c1cc(Cn2cncc2Oc2ccc(Br)cc2)ccn1-c1cncc(Cl)n1
Temperature: 60 °C

Procedure:
A mixture of 4-(4-bromophenyloxy)-1-trityl-1H-imidazole (0.164 g, 0.34 mmol) and 4-bromomethyl-1-(6-chloro-pyrazin-2-yl)-1H-pyridin-2-one from example 7 (98.5 mg, 0.34 mmol) in anhydrous acetonitrile (10 mL) was heated under reflux at 60° C. for 24 h. The resultant solution was concentrated, and the residue dissolved in a mixture of methanol (10 mL) and 1,2-dichloroethane (1 mL). The solution was heated under reflux for 2 h, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 1:1 v/v 6% methanol in chloroform and chloroform saturated with ammonia gas. Collection and concentration of appropriate fractions provided the titled compound.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[N:4]=1.[NH:24]1[CH2:28][CH:27]=[CH:26][CH2:25]1>CN(C)C=O>[CH3:23][N:14]1[C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:11]2[CH:10]=[N:9][C:8]([C:5]3[N:4]=[C:3]([CH2:2][N:24]4[CH2:28][CH:27]=[CH:26][CH2:25]4)[O:7][N:6]=3)=[C:12]2[CH2:13]1
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccccc2C1=O
Reactant: C1=CCNC1
Solvent: CN(C)C=O
Product: CN1Cc2c(-c3noc(CN4CC=CC4)n3)ncn2-c2ccccc2C1=O
Yield: 12.3 %

Procedure:
1.5 g (4.5 mmol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at 80° for 20 hours in 1 ml (14 mmol) 3-pyrroline and 30 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with methylene chloride/methanol 19/1 there was obtained 0.2 g (12%) of 5-methyl-3-[5-(3-pyrrolin-1-yl)methyl-1,2,4-oxadiazol-3-yl]-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, which was converted into the hydrochloride of m.p. 215°-220°.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[F:20][C:21]1[CH:22]=[C:23]([N:37]2[CH2:41][C@H:40]([CH2:42][NH:43][C:44](=[O:46])[CH3:45])[O:39][C:38]2=[O:47])[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1([OH:36])[CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(N(CC)CC)C.C[Si](C)(C)Cl>CN1CCCC1=O>[C:44]([NH:43][CH2:42][C@@H:40]1[O:39][C:38](=[O:47])[N:37]([C:23]2[CH:24]=[CH:25][C:26]([O:27][CH2:28][C:29]3([OH:36])[CH2:35][CH2:34][CH2:33][N:32]([C:2]4[N:11]=[C:10]5[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]5[CH:12]5[CH2:14][CH2:13]5)=[CH:4][C:3]=4[F:19])[CH2:31][CH2:30]3)=[C:21]([F:20])[CH:22]=2)[CH2:41]1)(=[O:46])[CH3:45]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(OCC3(O)CCCNCC3)c(F)c2)C(=O)O1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(=O)NC[C@H]1CN(c2ccc(OCC3(O)CCCN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)CC3)c(F)c2)C(=O)O1

Procedure:
In analogy to example 1 step 7 with 98 mg 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-[1,8]naphthyridine-3-carboxylic acid (MW: 282.66, 0.348 mmol), 138 mg N-{(5S)-3-[3-fluoro-4-(4-hydroxy-azepan-4-ylmethoxy)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (MW: 395.43, 0.348 mmol), 140 mg triethylamine (MW: 101.19, 1.39 mmol) and 113 mg trimethylchlorsilan (MW: 108.64, 1.04 mmol) in 1 ml N-methyl-pyrrolidin-2-one. Yield: 150 mg, 77%. MS: 642.7 (M+H)+, 640.7 (M+H)−, Method ESI+, ESI−.
Reaction SMILES: Br.[F:2][C:3]1[CH:16]=[CH:15][C:6]2[N:7]([CH2:11][CH2:12][O:13][CH3:14])[C:8](=[NH:10])[S:9][C:5]=2[CH:4]=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:27][CH3:28])=[C:22]([CH:26]=1)[C:23](O)=[O:24]>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:27][CH3:28])=[C:22]([CH:26]=1)[C:23](/[N:10]=[C:8]1\[S:9][C:5]2[CH:4]=[C:3]([F:2])[CH:16]=[CH:15][C:6]=2[N:7]\1[CH2:11][CH2:12][O:13][CH3:14])=[O:24]
Reactant: COc1ccc(Cl)cc1C(=O)O
Reactant: COCCn1c(=N)sc2cc(F)ccc21
Agent: Br
Product: COCCn1/c(=N/C(=O)c2cc(Cl)ccc2OC)sc2cc(F)ccc21

Procedure:
The product from Example 113A and 5-chloro-2-methoxybenzoic acid were processed using the methods described in Example 13 to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.24 (s, 3H), 3.79 (t, J=5.3 Hz, 2H), 3.83 (s, 3H), 4.65 (t, J=5.3 Hz, 2H), 7.17 (d, J=9.2 Hz, 1H), 7.41 (td, J=9.1, 2.5 Hz, 1H), 7.52 (dd, J=8.8, 2.7 Hz, 1H), 7.78 (dd, J=9.0, 4.2 Hz, 1H), 7.83 (d, J=2.7 Hz, 1H), 7.89 (dd, J=8.5, 2.7 Hz, 1H); MS (ESI+) m/z 395 (M+H)+; Anal. Calculated for C18H16ClFN2O3S: C, 54.75; H, 4.08; N, 7.09. Found: C, 54.29; H, 3.94; N, 6.99.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH:3]([C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=1)/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH2:13])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH:35]=O.[BH4-].[Na+]>CO>[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][NH:13][CH2:12][C:9]1[CH:10]=[CH:11][C:6](/[CH:5]=[CH:4]/[CH:3]([C:18]2[CH:19]=[C:20]([Cl:26])[C:21]([Cl:25])=[C:22]([Cl:24])[CH:23]=2)[C:2]([F:1])([F:27])[F:28])=[CH:7][C:8]=1[C:14]([F:16])([F:17])[F:15]
Reactant: O=Cc1ccccn1
Reactant: NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: FC(F)(F)c1cc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)ccc1CNCc1ccccn1
Reaction time: 1 h
Yield: 39.7 %

Procedure:
(E)-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)phenyl)methanamine (0.46 g, 1 mmol) was dissolved in CH3OH (3 mL). To this was added pyridine-2-carbaldehyde (0.107 g, 1 mmol). The reaction mixture was stirred for 1 h. After 1 h, NaBH4 (0.076 g, 2 mmol) was added and left at ambient temperature for 3 h. The reaction mixture was concentrated to give an oily residue. Purification by flash column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as a pale yellow liquid (0.22 g, 40%): 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J=4.8 Hz, 1H), 7.74 (m, 1H), 7.62 (m, 2H), 7.52 (m, 1H), 7.4 (s, 2H), 7.3 (m, 1H), 7.2 (m, 2H), 6.60 (d, J=16.0 Hz, 1H), 6.38 (dd, J=16.0, 8.0 Hz, 1H), 4.10 (m, 1H), 4.02 (s, 2H), 3.96 (s, 2H); ESIMS m/z 552.95 ([M+H]+); IR (thin film) 3338, 1114, 808 cm−1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.Br[CH2:13][CH:14]=[CH2:15].C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[CH2:15]([O:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10])[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: Cc1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C=CCOc1ccc(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-methyl-2-nitrophenol (5.0 g, 0.033 mol), 3-bromoprop-1-ene (4.2 g, 0.034 mol) and K2CO3 (4.6 g, 0.033 mol) in acetone (20 mL) was stirred for 8 h at ambient temperature. The mixture was poured into water (50 mL), extracted with EtOAc (90 mL), washed with brine, dried and concentrated to give the title compound (7a).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:30][CH3:31])[C:9]3[C:14]([O:15][CH2:16][C@H:17]4[O:22][CH2:21][CH2:20][NH:19][CH2:18]4)=[CH:13][N:12]=[C:11]([C:23]#[C:24][C:25]([CH3:28])([OH:27])[CH3:26])[C:10]=3[N:29]=2)=[N:4][O:5][N:6]=1.[CH:32](=O)[CH3:33].C(O)(=O)C.[BH3-]C#N.[Na+].C([O-])(O)=O.[Na+]>CO>[NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:30][CH3:31])[C:9]3[C:14]([O:15][CH2:16][C@H:17]4[O:22][CH2:21][CH2:20][N:19]([CH2:32][CH3:33])[CH2:18]4)=[CH:13][N:12]=[C:11]([C:23]#[C:24][C:25]([CH3:26])([OH:27])[CH3:28])[C:10]=3[N:29]=2)=[N:4][O:5][N:6]=1
Reactant: CCn1c(-c2nonc2N)nc2c(C#CC(C)(C)O)ncc(OC[C@@H]3CNCCO3)c21
Reactant: CC=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCN1CCO[C@H](COc2cnc(C#CC(C)(C)O)c3nc(-c4nonc4N)n(CC)c23)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.2 %

Procedure:
To a solution of the compound of Example 4 (0.13 g, 0.30 mmol) in MeOH (4 mL) at 0° C. was added acetaldehyde (0.034 mL, 0.61 mmol) and acetic acid (0.052 mL. 0.90 mmol). This was followed by the addition of NaCNBH3 (0.048 g, 0.76 mmol). The reaction was allowed to warm to RT. After 18 h, the reaction was poured into 50% aq. NaHCO3. The solution was cooled to 0° C. and the resultant precipitate was collected to give 0.10 g of the desired compound. MS (ES+) m/z 456.4 (M+H)+.
Reaction SMILES: [C:1]([O-:14])(=[O:13])[CH2:2][CH2:3]CCCCCCCCC.[C:15]([O-])(=[O:27])[CH2:16]CCCCCCCCCC.[CH2:29]([Sn+2]CCCC)CCC.C1CCCCC1>C1COCC1>[CH3:29][C:2]([C:1]([O:14][CH2:16][CH2:15][OH:27])=[O:13])=[CH2:3]
Reactant: CCCC[Sn+2]CCCC
Reactant: CCCCCCCCCCCC(=O)[O-]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: C=C(C)C(=O)OCCO
Temperature: 40 °C

Procedure:
A three-neck reaction flask fitted with a mechanical stirrer, condenser, dropping funnel, and thermometer was charged with 76 parts of a 32.4% THF solution of Polymer D followed by (0.25 parts) of dibutyltin dilaurate (Sigma-Aldrich) and 0.01 parts of BHT. A solution of IEM (4.77 parts) in THF (10 parts) was slowly added from the dropping funnel and the resulting solution heated at 40° C. for 30 minutes. The resulting polymer solution was cooled to room temperature, poured into a large excess of cyclohexane (approximately 5 times volume of reaction mixture), and the precipitated solid collected by filtration and dried in a 30° C. vacuum oven. The dried white solid was designated Example 2 and identified as the polymer of NIPAAM/HEMA with a plurality of the HEMA monomeric units derivatized with IEM to provide monomeric units of the following structure (Me=CH3):
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.ClC(Cl)(Cl)Cl>O>[Br:13][CH2:8][C:7]1[CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=[C:3]([CH3:12])[C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc(CBr)c1Cl
Reaction time: 2 h
Yield: 70.7 %

Procedure:
A mixture of 129 g of 2-chloro-1,3-dimethyl-5-nitrobenzene, 125 g of 1-bromo-2,5-pyrrolidinedione, 12 g of dibenzoyl peroxide and 1200 ml of tetrachloromethane was stirred for 2 hours at reflux temperature using a water separator. Twice there was added an extra portion of 20 g of dibenzoyl peroxide during a refluxing period of 29 hours. After cooling, the reaction mixture was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /hexane 50:50). The eluent of the desired fraction was evaporated, yielding 130 g (70.2%) of 1-(bromomethyl)-2-chloro-3-methyl-5-nitrobenzene (interm. 5).
Reaction SMILES: [CH:1]1([C:8]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][CH3:19])[CH:11]=2)=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(C1(C2C=C(OC)C=C(OC)C=2)[S:28][CH2:27][CH2:26][S:25]1)CCC>CCCCCC.C(OCC)(=O)C>[CH:1]1([C:8]2([C:10]3[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][CH3:19])[CH:11]=3)[S:28][CH2:27][CH2:26][S:25]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(OC)cc(C(=O)C2CCCCCC2)c1
Reactant: CCCCC1(c2cc(OC)cc(OC)c2)SCCS1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc(OC)cc(C2(C3CCCCCC3)SCCS2)c1

Procedure:
Compound 12 was prepared from Compound 8 using the same procedure as described above for Compound 9. Yield 3.60 g (79.2%) as an oil. Rf=0.56 (hexane:ethyl acetate 92:8); IR (neat) 2925, 1206, 1067, 832, 693 cm−1; 1H NMR δ 6.94 (d, J=2.4 Hz, 2H), 6.32 (t, J=2.25 Hz, 1H), 3.80 (s, 6H), 3.31–3.10 (m, 4H), 2.40–2.32 (m, 1H), 1.96–1.30 (m, 12H). 13C NMR δ 160.38, 148.94, 106.52, 98.48, 81.99, 70.21, 55.60, 51.27, 45.22, 39.34, 32.82, 29.80, 28.04, 27.77; MS: (ESI, Pos.) m/z 361 ([M+23]+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]([CH2:30][CH2:31][CH3:32])[CH:9]2[CH2:18][C:17]3[CH:16]=[C:15]([O:19][S:20]([C:23]4[C:24]([CH3:29])=[N:25][O:26][C:27]=4[CH3:28])(=[O:22])=[O:21])[CH:14]=[CH:13][C:12]=3[CH2:11][CH2:10]2)[CH2:3][CH2:2]1.C(OC([N:40]1[CH2:45][CH2:44][CH:43]([C:46](O)=[O:47])[CH2:42][CH2:41]1)=O)(C)(C)C.CCN=C=NCCCN(C)C.C(N(CC)CC)C>ClCCl>[NH:40]1[CH2:45][CH2:44][CH:43]([C:46]([N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][N:8]([CH2:30][CH2:31][CH3:32])[CH:9]3[CH2:18][C:17]4[CH:16]=[C:15]([O:19][S:20]([C:23]5[C:24]([CH3:29])=[N:25][O:26][C:27]=5[CH3:28])(=[O:22])=[O:21])[CH:14]=[CH:13][C:12]=4[CH2:11][CH2:10]3)[CH2:3][CH2:2]2)=[O:47])[CH2:42][CH2:41]1
Reactant: CCCN(CC1CCNCC1)C1CCc2ccc(OS(=O)(=O)c3c(C)noc3C)cc2C1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(CC1CCN(C(=O)C2CCNCC2)CC1)C1CCc2ccc(OS(=O)(=O)c3c(C)noc3C)cc2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.7 %

Procedure:
Under an inert atmosphere 3,5-dimethyl-isoxazole-4-sulfonic acid 7-(piperidin-4-ylmethyl-propyl-amino)-5,6,7,8-tetrahydro-naphthalen-2-yl ester (400 mg, 0.87 mmol), piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (199 mg, 0.87 mmol, 1 eq.), EDCI (166 mg, 0.87 mmol, 1 eq.), triethylamine (0.25 mL, 1.79 mmol, 2 eq.), and dichloromethane (35 mL) were combined. The mixture was stirred at room temperature for 48 h and then concentrated in vacuo. The residue was taken up in EtOAc (50 mL) and washed with water (30 mL), 1N NaOH (30 mL), brine (30 mL), and then dried (MgSO4). The solution was filtered and concentrated to afford a yellow oil. The oil was flash chromatographed on silica gel eluting with 20% acetone in hexanes to afford the protected amine as a foam (447 mg), which was deprotected with trifluoroacetic acid, as described herein, to afford 3,5-dimethyl-isoxazole-4-sulfonic acid 7-{[1-(piperidine-4-carbonyl)-piperidin-4-ylmethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-yl ester (320 mg), 114M+H]+=609.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:7]([C:16](N(OC)C)=[O:17])[N:6]=1)([CH3:4])[CH3:3].[CH3:22][Si:23]([CH3:32])([CH3:31])[C:24]#[C:25][CH2:26][CH2:27][CH2:28][Mg]Br>O1CCCC1>[CH3:15][C:12]([C:9]1[C:10]([OH:11])=[C:5]([C:2]([CH3:3])([CH3:1])[CH3:4])[N:6]=[C:7]([C:16](=[O:17])[CH2:28][CH2:27][CH2:26][C:25]#[C:24][Si:23]([CH3:32])([CH3:31])[CH3:22])[N:8]=1)([CH3:13])[CH3:14]
Reactant: C[Si](C)(C)C#CCCC[Mg]Br
Reactant: CON(C)C(=O)c1nc(C(C)(C)C)c(O)c(C(C)(C)C)n1
Solvent: C1CCOC1
Product: CC(C)(C)c1nc(C(=O)CCCC#C[Si](C)(C)C)nc(C(C)(C)C)c1O
Reaction time: 16 h
Yield: 76.6 %

Procedure:
To a solution of 4,6-bis(1,1-dimethylethyl)-5-hydroxy-N-methoxy-N-methyl-2-pyrimidinecarboxamide (1,00 g, 3.38 mmols) in tetrahydrofuran (50 mL) under nitrogen atmosphere is added a freshly prepared 0.105M solution of 5-trimethylsilylpent-4-ynyl magnesium bromide (81 mL, 8.5 mmols) [from 5-bromo-1-trimethylsilyl-1pentyne (3.86 g, 17.5 mmol) and magnesium (1.50 g, 61.7 mg-atom) in tetrahydrofuran (140 mL)] dropwise. After stirring 16 hours, the resulting mixture is quenched with saturated aqueous ammonium chloride solution and extracted with ethyl ether. The combined extracts are washed with brine and the organic phase is dried over magnesium sulfate. Concentration under vacuum is followed by purification of the organic residue by flash chromatography (SiO2, 20% ethyl acetate/hexane) to give 0.97 g (77%) of the title compound which is used without further purification to make the compound of Example 7.
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:22]([O:24][P:25]([CH:30](O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:29])[O:26][CH2:27][CH3:28])[CH3:23].N1C=CC=CC=1>C(Cl)Cl>[CH2:22]([O:24][P:25]([CH:30]([Br:1])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:29])[O:26][CH2:27][CH3:28])[CH3:23]
Reactant: BrBr
Reactant: CCOP(=O)(OCC)C(O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOP(=O)(OCC)C(Br)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
90 g of bromine, dissolved in 250 ml of methylene chloride, were added dropwise to a solution of 131 g (0.5 mole) of triphenylphosphine in 500 ml of methylene chloride at 30° to 35° C., moisture being excluded. The mixture was subsequently stirred at room temperature for 1 hour, a solution of 122 g (0.5 mole) of α-hydroxybenzyl-phosphonic acid diethyl ester in 250 ml of methylene chloride was then added dropwise at -20° C. in the course of 1 hour, the mixture was subsequently stirred at -20° C. for 1 hour and 40 g of pyridine, dissolved in 250 ml of methylene chloride, were then added dropwise at -20° C. in the course of one hour. The mixture was subsequently stirred for 20 hours, whereupon the temperature rose slowly to +20° C. The reaction mixture was transferred to a pear-shaped flask and the solvent was distilled off under a waterpump vacuum. The residue was extracted by stirring with one liter of ether and the undissolved triphenylphosphine oxide was filtered off (120 g of triphenylphosphine oxide=86% of theory). The mother liquor was concentrated in vacuo and the residue distilled under a high vacuum. 112 g (72% of theory) of α-bromobenzylphosphonic acid diethyl ester were obtained as a light yellow oil with a boiling point of 110° C./0.01 mm Hg and a purity of 95.9% (gas chromatogram).
Reaction SMILES: C[O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[O:6]1)[CH2:12]2)=[O:4].[OH-].[Na+]>CO.O>[C:5]12([C:3]([OH:4])=[O:2])[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[O:6]1)[CH2:12]2
Reactant: COC(=O)C12CC3CC(CC(C3)O1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C12CC3CC(CC(C3)O1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.6 %

Procedure:
To a solution of Example 81A (2.5 g, 12.6 mmol) in methanol/water (1:1, 100 mL) was added 5 N aqueous NaOH (3.8 mL, 19 mmol). The mixture was stirred at room temperature for 3 hours and then extracted with methylene chloride to remove unreacted starting material. The aqueous layer was acidified (pH˜2) with 6 N aqueous HCl and then extracted with methylene chloride. The combined acidic extracts were dried (Na2SO4), filtered and concentrated to afford 1.92 g of the title compound. MS (ESI+) m/z 183 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH2:11](Cl)Cl>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:11])=[O:7])=[CH:4][N:3]=1
Reactant: ClCCl
Reactant: O=C(O)c1ccc(Cl)nc1
Product: COC(=O)c1ccc(Cl)nc1
Reaction time: 8 h

Procedure:
An ethereal solution of CH2N2 (0.1 mole) is added to a suspension of 6-chloronicotinic acid (15 g) in CH2Cl2 until bubbling ceases. The reaction mixture is stirred overnight, evaporated and dried in vacuo affording the desired product as an off-white solid. M.P.=83°-85° C.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].[Cl:5][C:6]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:7]=1[CH:8]=[CH:9][N+:10]([O-:12])=[O:11]>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:7]=1[C@H:8]1[C@H:9]([N+:10]([O-:12])=[O:11])[CH2:4][CH:3]=[CH:2][CH2:1]1
Reactant: C=CC=C
Reactant: O=[N+]([O-])C=Cc1ccc(F)cc1Cl
Solvent: Cc1ccccc1
Product: O=[N+]([O-])[C@@H]1CC=CC[C@H]1c1ccc(F)cc1Cl
Temperature: 110 °C
Reaction time: 72 h

Procedure:
A 10 mL solution of 1:1 1,3-butadiene in toluene stored at −20° C. and 2-chloro-4-fluoro-β-nitrostyrene (2.0 g, 10 mmol) were added to a pressure tube and sealed. The solution was heated to 110° C. and stirred for three days. The reaction mixture was cooled to room temperature, concentrated and the residue was crystallized from hexanes to give the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.23-7.28 (m, 1H), 7.11-7.25 (m, 3H), 6.94-7.01 (m, 1H), 5.73-5.83 (m, 2H), 5.04-5.13 (m, 1H), 3.99-4.08 (m, 1H), 2.71-2.82 (m, 2H), 2.51-2.61 (m, 1H), 2.15-2.26 (m, 1H).