Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][As-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S+:15]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22].C(N([CH2:35][CH3:36])CC)C.[O:37]([CH:44]([O:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)Cl)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O1CCCC1>[F:1][As-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[O:37]([CH:44]([O:46][C:36]1[CH:35]=[CH:52][CH:47]=[CH:48][CH:49]=1)[O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[S+:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH:44]([O:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[O:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH:44]([O:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: ClC(Oc1ccccc1)Oc1ccccc1
Reactant: CCN(CC)CC
Reactant: Oc1ccccc1[S+](c1ccccc1O)c1ccccc1O
Agent: F[As-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: c1ccc(OC(Oc2ccccc2)Oc2ccccc2[S+](c2ccccc2OC(Oc2ccccc2)Oc2ccccc2)c2ccccc2OC(Oc2ccccc2)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
20 parts of tris(hydroxyphenyl)sulfonium hexafluoroarsenate are dissolved in 100 parts of tetrahydrofuran. 12.2 parts of triethylamine are added, followed dropwise by the gradual addition of 30 parts of diphenoxychloromethane, and the mixture is stirred at room temperature for 24 hours. The mixture is then washed with water, and the organic solution is dried over a molecular sieve and evaporated in a rotary evaporator. Chromatographic purification leaves 14.8 parts of the expected product. IR and NMR agree with the expected structure.
Reaction SMILES: [CH:1]([CH:19]1[CH2:24][C:23](=[O:25])[NH:22][C:20]1=[O:21])=[CH: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][CH3:18].C=O.[C:28](=O)(O)[O-:29].[Na+].Cl>O.CCCCCCC>[OH:29][CH2:28][N:22]1[C:23](=[O:25])[CH2:24][CH:19]([CH:1]=[CH: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][CH3:18])[C:20]1=[O:21]
Reactant: CCCCCCCCCCCCCCCCC=CC1CC(=O)NC1=O
Reactant: O=C([O-])O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CCCCCCC
Solvent: O
Product: CCCCCCCCCCCCCCCCC=CC1CC(=O)N(CO)C1=O
Temperature: 70 °C

Procedure:
In a reaction vessel was placed 1 liter of heptane and 550 grams of octadecenyl succinimide. The mixture was heated to 70° C. with stirring and a mixture of 137 grams of 36% aqueous formaldehyde and 22 grams of sodium bicarbonate was added. This mixture was stirred at reflux for 4 hours. Then 300 ml of water was added and the mixture neutralized with hydrochloric acid. The aqueous layer was separated and removed, then 500 ml butanol was added to the organic layer and the mixture washed with hot water. The organic layer was separated and heptane, butanol and residual water distilled off leaving as the product N-hydroxymethyl-n-octadecenyl succinimide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[NH2:14])[O:7][CH:8](O)[CH3:9])([O-:3])=[O:2].C(=O)([O-])[O-:16].[Ca+2].Cl[C:21]([O:23][CH2:24][CH2:25][Cl:26])=[O:22]>O1CCOCC1>[N+:1]([C:4]1[CH:5]=[C:6]([O:7][CH2:8][CH2:9][OH:16])[CH:11]=[CH:12][C:13]=1[NH:14][C:21](=[O:22])[O:23][CH2:24][CH2:25][Cl:26])([O-:3])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: O=C(Cl)OCCCl
Reactant: CC(O)Oc1ccc(N)c([N+](=O)[O-])c1
Agent: [Ca+2]
Solvent: C1COCCO1
Product: O=C(Nc1ccc(OCCO)cc1[N+](=O)[O-])OCCCl
Temperature: 90 °C

Procedure:
4 mols (792 g) of 3-nitro-4-aminophenoxyethanol are dissolved in 1,600 ml of dioxane. 2.4 mols (240 g) of calcium carbonate are added. The temperature is raised to about 90° C. and 4.8 mols (686 g) of β-chloroethyl chloroformate are then introduced gradually, whilst stirring. When the addition has ended, heating is maintained for 30 minutes at 90° C. The reaction medium is filtered hot. The cooled filtrate is diluted with petroleum ether to precipitate the desired product, which, after recrystallisation from dioxane and drying in vacuo, melts at 119° C.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:21][C:20](=[O:22])[CH:19]=[C:18]([OH:23])[CH2:17]2)=[CH:12][CH:11]=1)(C)(C)C.[C:34]([C:38]1[CH:43]=[C:42]([O:44][CH2:45][CH2:46][O:47][Si](C(C)(C)C)(C)C)[C:41]([CH3:55])=[CH:40][C:39]=1[S:56]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:37])([CH3:36])[CH3:35].C([O-])([O-])=O.[K+].[K+].Cl>CO.CN(C=O)C>[C:34]([C:38]1[CH:43]=[C:42]([O:44][CH2:45][CH2:46][OH:47])[C:41]([CH3:55])=[CH:40][C:39]=1[S:56][C:19]1[C:20](=[O:22])[O:21][C:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][OH:6])=[CH:11][CH:12]=2)([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:17][C:18]=1[OH:23])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(C2(CCc3ccccc3)CC(O)=CC(=O)O2)cc1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(OCCO[Si](C)(C)C(C)(C)C)cc2C(C)(C)C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc(SC2=C(O)CC(CCc3ccccc3)(c3ccc(OCCO)cc3)OC2=O)c(C(C)(C)C)cc1OCCO

Procedure:
To a round bottom flask equipped with a magnetic stirrer were added 6-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-phenyl} -4-hydroxy-6-phenethyl-5,6-dihydro-pyran-2-one (prepared in Example SS; 0.260 g, 0.555 mmol), toluene-4-thiosulfonic acid S-{2-tert-butyl-4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-methyl-phenyl) ester (prepared in Example PPP; 0.282 g, 0.555 mmol), K2CO3 (0.346 g, 2.50 mmol), and DMF (5 mL), as described in General Method 9. The mixture was stirred at room temperature for 2 days at which time MeOH (150 mL) was added and the solution taken to pH 3.0 with conc. HCl. The reaction was quenched with H2O (500 mL) and extracted with EtOAc. The organics were dried over MgSO4 and concentrated; the residue was taken up in a small amount of EtOAc and triturated with hexane. The solid was filtered and dried under high vacuum to yield the title compound, m.p. >190° C. (dec.). 1H NMR (DMSO-d6) δ 1.45 (s, 9 H), 1.68 (s, 3 H), 2.22 (br m, 4 H), 2.51 (br m, partially obscured by DMSO, 2 H), 3.34 (d of ABX q, partially obscured by H2 0, 1 H), 3.40 (d of ABX q, partially obscured by H2O, 1 H), 3.67 (br m, 2 H), 3.72 (br m, 2 H)3.91 (t, 2 H), 3.98 (t, 2 H), 6.76 (s, 1 H), 6.96 (s, 1 H), 6.99 (d, 2 H), 7.08-7.22 (m, 1 H), 7.10 (d, 2 H), 7.24 (d, 2 H), 7.30 (d, 2 H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4](Cl)[N:3]=1.Cl.[CH3:13][O:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH2:23])=[CH:18][CH:17]=1.C([O-])(O)=O.[Na+]>O>[CH3:13][O:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:4]2[N:3]=[C:2]([Cl:1])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][NH:8]3)=[CH:18][CH:17]=1
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Reactant: COC(=O)c1ccc(CN)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc(CNc2nc(Cl)nc3[nH]cnc23)cc1
Temperature: 100 °C
Yield: 59.4 %

Procedure:
A suspension of 2,6-dichloro-9H-purine (1 g, 5.29 mmol), 4-aminomethyl-benzoic acid methyl ester hydrochloride (1.2 equiv., 1.28 g) and NaHCO3 (2.1 equiv., 935 mg) in water was heated at 100° C. The homogeneous solution thus formed was refluxed 30 min. The resulting white precipitate was filtered, washed with cold water and dried under vacuum giving the title compound 241 (1 g, 3.14 mmol, 60%). LRMS calc:317.7, found: 318.3 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29](O)=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].CN(C(ON1N=NC2C=[CH:46][CH:47]=[N:48][C:43]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.N1CCC1.Cl>CN(C=O)C.O>[N:48]1([C:29]([C:26]2[CH:25]=[C:24]([C:20]3[CH:19]=[C:18]([O:17][C:16]4[CH:32]=[CH:33][C:13]([NH:12][C:10]([NH:9][C:3]5[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=5[F:1])=[O:11])=[CH:14][CH:15]=4)[CH:23]=[CH:22][N:21]=3)[NH:28][CH:27]=2)=[O:30])[CH2:47][CH2:46][CH2:43]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
Agent: C1CNC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)N5CCC5)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (100 mg, 0.22 mmol), HATU (99 mg, 0.26 mmol) and N,N-diisopropylethylamine (62 mg, 0.48 mmol) in anhydrous DMF (10 ml) was stirred at room temperature for 10 minutes, followed by addition of azetidine (20 mg, 0.35 mmol). The mixture was stirred for another 5 minutes and poured into 100 ml of water. 2M HCl was added dropwise until pH=4˜5. The precipitates were filtered, washed with water and dried in vacuo to give 1-[4-({2-[4-(azetidin-1-ylcarbonyl)-1H-pyrrol-2-yl]pyridin-4-yl}oxy)phenyl]-3-(2-fluoro-5-methylphenyl)urea as light brown solid. Yield: 95 mg, 87%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:24][CH3:25])=[C:16]([O:22][CH3:23])[C:17]=3[N+:19]([O-])=O)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH4+].[Cl-].O.C(Cl)(Cl)Cl>CO.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:17]([NH2:19])=[C:16]([O:22][CH3:23])[C:15]([O:24][CH3:25])=[CH:14][C:13]=3[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Br)c3)c2c([N+](=O)[O-])c1OC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: COc1cc2ncnc(Nc3cccc(Br)c3)c2c(N)c1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (3-bromo-phenyl)-(6,7-dimethoxy-5-nitro-quinazolin-4-yl)-amine (0.2 g, 0.49 mmol) (from Example 6, Step A, supra) and NH4Cl (0.26 g, 4.94 mmol) in a mixture of MeOH, H2O and CHCl3 (30 mL, 6:1:1) was added Zn powder (0.64 g, 9.87 mmol). The reaction mixture was stirred at room temperature for 3 hours. The mixture was then filtered, the filtrate was concentrated and then extracted with chloroform (100 mL). The organic layer was separated, dried over Na2SO4, and concentrated. This residue was purified by chromatography using EtOAc/CH2Cl2 /NEt3 (1:1:0.05) as eluent to give the desired N4-(3-bromo-phenyl)-6,7-dimethoxy-quinazoline-4,5-diamine as a yellow gum. (Yield 0.1 g, 54%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]=[CH:9][CH:10]2[C:15](=[O:16])OC(C)(C)OC2=O)[CH:5]=[N:6][CH:7]=1.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:15]([OH:16])=[CH:10][CH:9]=[N:8]2)=[N:6][CH:7]=1
Reactant: CC1(C)OC(=O)C(C=Nc2cncc(Br)c2)C(=O)O1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Oc1ccnc2cc(Br)cnc12
Temperature: 236.5 °C
Yield: 76 %

Procedure:
5-{[(5-Bromopyridin-3-yl)imino]methyl}-2,2-dimethyl-1,3-dioxane-4,6-dione (59 g, 0.18 mol) was slowly added to DOWTHERM A heat transfer fluid (2000 mL) over a period of 5 minutes at 235-238° C. Following addition, the reaction was maintained for an additional 5 minutes and then allowed to cool to 40° C. A brown precipitate formed, which was filtered and washed with hexanes (150 mL). The brown solid was suspended in an ethanol/water mixture (90:10, 1500 mL), heated to a boil for 30 minutes, isolated by filtration, and washed with ethanol (200 mL) to yield 30.8 g of 7-bromo[1,5]naphthyridin-4-ol as a dark brown powder. 1H NMR (300 MHz, CDCl3) δ 11.81 (br s, 1H), 8.69 (d, J=1.9 Hz, 1H), 8.21 (d, J=1.9 Hz, 1H), 7.95 (d, J=7.7 Hz, 1H), 6.22 (d, J=7.5 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:11]=[CH:10][CH:9]=[C:5]([C:6]([OH:8])=O)[C:4]=1[NH2:12].O=S(Cl)Cl.[Cl:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22].C(Cl)(Cl)Cl>C1C=CC=CC=1>[NH2:12][C:4]1[C:3]([C:2]([F:1])([F:14])[F:13])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=1[Cl:19])=[O:8]
Reactant: Nc1c(C(=O)O)cccc1C(F)(F)F
Reactant: Nc1ccccc1Cl
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: Nc1c(C(=O)Nc2ccccc2Cl)cccc1C(F)(F)F
Yield: 77.6 %

Procedure:
Prepared according to Procedure A using 3-trifluoromethylanthranilic acid (2.0 g, 9.75 mmol) and SOCl2 (1.8 mL, 24.4 mmol) in benzene (50 mL), followed by 2-chloroaniline (2.1 mL, 19.5 mmol) and CHCl3 (50 mL). The product was purified by recrystallization from MeOH to provide 2.38 g yellow crystals (78%). 1H NMR (CDCl3) δ: 8.40 (dd, J=1.4, 8.3 Hz, 1H); 8.25 (br s, 1H); 7.71 (d, J=7.8 Hz, 1H); 7.60 (d, J=7.8 Hz, 1H); 7.43 (dd, J=1.4, 8.0 Hz, 1H); 7.34 (dt, J=1.3, 7.9 Hz, 1H); 7.11 (dt, J=1.5, 7.7 Hz, 1H); 6.77 (t, J=7.8 Hz, 1H); 6.24 (br S, 2H). MS (ES): m/z 315.0 (M+)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[C:8]([CH3:16])[N:9]=[CH:10]2.[Br:18]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[C:8]([CH2:16][Br:18])[N:9]=[CH:10]2
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1c(Cl)ccc2cnc(C)cc12
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)Cc1c(Cl)ccc2cnc(CBr)cc12
Temperature: 40 °C
Yield: 40 %

Procedure:
To a solution of (6-Chloro-3-methyl-isoquinolin-5-yl)-acetic acid methyl ester (1.9 g, 7.63 mmol) in tetrachloromethane (190 mL) was added N-bromosuccinimide (1.36 g, 7.63 mmol). The reaction mixture was heated to 40° C. for 1 h under simultaneous irradiation by a 300 W UV lamp, filtered and the filtrate concentrated in vacuo. The crude product was purified by flash column chromatography (silica gel, cyclohexane/EtOAc 80:20) to afford the title compound as a white powder (1.00 g, 3.05 mmol, 40%). MS (ES+): 328 (M(C13H1179Br35ClNO2)+H)+.
Reaction SMILES: C(O[CH:5]1[O:11][C@H:10]([CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@:8](CC2C=CC=CC=2)([OH:9])[C@:6]1([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[OH:7])(=O)C.CO.[CH3:37][C:38]([OH:40])=[O:39]>[Pd].N1C=CC=CC=1>[C:38]([O:40][C@H:5]1[O:11][C@H:10]([CH2:8][OH:9])[C@@H:12]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@:6]1([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[OH:7])(=[O:39])[CH3:37]
Reactant: CC(=O)O
Reactant: CC(=O)OC1O[C@H](COCc2ccccc2)[C@](O)(Cc2ccccc2)[C@@]1(O)Cc1ccccc1
Agent: [Pd]
Solvent: c1ccncc1
Solvent: CO
Product: CC(=O)O[C@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@@]1(O)Cc1ccccc1
Yield: 39 %

Procedure:
To a solution of acetate (V) (20.6 g, 4.46 mmol) in a 1:1 solution of MeOH/HOAc (100 ml) was added 2.0 g of 10% Pd/C and 82 μl of pyridine (0.4%). The solution was shaken on a Parr apparatus under 50 psig of H2. After 24 h the solution was filtered and concentrated, and the residue was purified on a Waters Prep-500 HPLC (EtOAc/hexane, 22/78) to yield 6.4 g of a light yellow oil (39%), homogeneous by TLC. This reaction routinely gave yields of 35-40%. The point at which the reaction is removed from the hydrogenator is determined by when the selectively reduced compound appears greatest by TLC analysis. 1H NMR (CDCl3)δ: 7.3 (s, 10H), 6.2 (br s, 1H), 3.6-4.7 (m, 9H), 2.10 (s, 3H). 13C NMR (CDCl3) δ: 169.9, 137.5, 137.1, 128.5 (4C), 128.0 (4C), 127.7 (2C), 100.4 (αC-1), 86.8, 84.6, 82.8, 72.4, 72.1, 62.1, 21.2 Elemental Analysis: Calculated for C21H24O6 : C, 67.73; H, 6.50. Found: C, 67.49; H, 6.50.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[CH3:17][C:18]1[C:23]([F:24])=[C:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[N:21]=[C:20](F)[C:19]=1[F:37]>C(OCC)C>[F:24][C:23]1[C:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=2)=[N:21][C:20]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[C:19]([F:37])[C:18]=1[CH3:17]
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: Cc1c(F)c(F)nc(Oc2cccc(C(F)(F)F)c2)c1F
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1c(F)c(Oc2cccc(C(F)(F)F)c2)nc(-c2ccc(C(F)(F)F)cc2)c1F
Temperature: 10 °C
Reaction time: 1 h

Procedure:
Butyl lithium (2.6 ml, 6.6 mmol, 2.5 M solution in hexane) is added to a solution of 1-bromo-4-trifluoromethyl benzene (0.84 ml, 6 mmol) in anhydrous diethyl ether (5 ml) at −30° C. The mixture is stirred for 60 min at −20° C. and for 60 min at 10° C. The solution is allowed to warm to ambient temperature. This solution is then added to a mixture of 4-methyl-2,3,5-trifluoro-6-(3-trifluoromethylphenoxy)pyridine 2A (1.5 g, 5 mmol) in anhydrous diethyl ether (100 ml) at −50° C. during 2.5 hours. The mixture is further stirred for 7 hours at −50° C. and washed with saturated aqueous ammonium chloride and water. After drying and evaporation of the organic layer, the residue is purified by vacuum destillation. One obtains colorless crystals (0.37 g, 0.85 mmol, bp. 130° C. at 0.01-0.02 mbar) of mp. 87° C.
Reaction SMILES: ClC1C(Cl)=CC(NC2C3C(=CC(OCCOCC[O:29][S:30]([CH3:33])(=O)=[O:31])=C([N+]([O-])=O)C=3)N=CN=2)=C(F)C=1.[Cl:35][C:36]1[C:41]([Cl:42])=[CH:40][C:39]([NH:43][C:44]2[C:53]3[C:48](=[CH:49][C:50]([O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][OH:69])=[C:51]([N+:54]([O-:56])=[O:55])[CH:52]=3)[N:47]=[CH:46][N:45]=2)=[C:38]([F:70])[CH:37]=1.CS(Cl)(=O)=O.C(N(CC)CC)C>ClCCl>[Cl:35][C:36]1[C:41]([Cl:42])=[CH:40][C:39]([NH:43][C:44]2[C:53]3[C:48](=[CH:49][C:50]([O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][O:69][S:30]([CH3:33])(=[O:31])=[O:29])=[C:51]([N+:54]([O-:56])=[O:55])[CH:52]=3)[N:47]=[CH:46][N:45]=2)=[C:38]([F:70])[CH:37]=1
Reactant: CS(=O)(=O)OCCOCCOc1cc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2cc1[N+](=O)[O-]
Reactant: O=[N+]([O-])c1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1OCCOCCOCCOCCO
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOCCOCCOCCOc1cc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2cc1[N+](=O)[O-]

Procedure:
Compound 32b was prepared as described hereinabove for Compound 32a, using Compound 29b (0.023 gram, 0.043 mmol), methanesulfonyl chloride (0.014 gram, 0.12 mmol) and triethylamine (0.021 gram, 0.021 mmol) in dichloromethane (2.3 ml), yielding 0.015 gram of the product (55% yield).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:30]=[CH:29][C:19]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)=[O:21])=[CH:18][CH:17]=1.C>CCCCCC.O>[F:28][C:24]1[CH:23]=[C:22]([C:20]([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[CH:30][CH:29]=2)=[O:21])[CH:27]=[CH:26][CH:25]=1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: Nc1ccc(C(=O)c2cccc(F)c2)cc1
Agent: C
Solvent: O
Solvent: CCCCCC
Solvent: O=S(Cl)Cl
Product: CC(O)(C(=O)Nc1ccc(C(=O)c2cccc(F)c2)cc1)C(F)(F)F
Reaction time: 1 h

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.58 g, 10 mmol) in N,N-dimethylcetamide (15 mL) was added thionyl chloride (1.25 g, 10.5 mmol) and the mixture stirred at -20° to -10° C. for 1 hour. 4-Amino-3'-fluorobenzophenone (1.44 g, 6.7 mmol) was added in one portion and the reaction mixture stirred at room temperature overnight. The mixture was poured into water to yield an oil and a cloudy solution. The cloudy solution was decanted from the oil and filtered by suction through a pad of Celite. The Celite pad was washed with methylene chloride and the solution added to a solution of the gum in methylene chloride. The solution was dried (MgSO4), filtered and the solvent removed in vacuo. The resulting oil was chromatographed on silica gel (ethyl ether), the proper fractions combined and the solvent removed to yield an oil. The oil was dissolved in 50 mL of hexane containing enough methylene chloride to give a clear solution and the solution concentrated on a steambath until the solution became cloudy. The resulting pale yellow solid was collected by filtration and dried to yield 1.51 g (63%) of N-[4-(3-fluorophenylcarbonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylproanamide, mp 121.5°-3° C. 1H-NMR (250 MHz, d6-DMSO): 1.59 (s, 3H, CH3) 3.32 (s, 1H, OH) 7.46-7.60 (m, 4H, aromatic) 7.75 (d, 2H, J=9.1 Hz aromatic) 7.96 (d, 2H, J=8.2 Hz, aromatic) 10.33 (s, 1H, NH). MS (CI, CH4): 356 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=C[CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[N:22]1C=CC=C2C(N)CCC=12>>[CH2:1]([C:3]1[C:4]([NH:11][CH:12]2[C:20]3[C:15](=[N:22][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: NC1CCc2ncccc21
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: CCc1cnc(CC)c(NC2CCc3ncccc32)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 6,7-dihydro-5H-cyclopenta[b]pyridin-5-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 8.48, 7.73, 7.66, 7.14, 5.82, 4.54, 3.22–3.07, 2.79, 2.70–2.57, 1.94 1.36–1.27; HRMS (FAB) calcd for C16H20N4+H 269.1766, found 269.1763.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Br:11]N1C(=O)CCC1=O>CN(C)C=O.O>[Br:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:1][CH2:2][CH2:3][CH2:4]2
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2c(c1)CCCN2
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc2c(c1)CCCN2
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of 1,2,3,4-tetrahydroquinoline (100 mg) in N,N-dimethylformamide (1 ml), a solution of N-bromosuccinimide (134 mg) in N,N-dimethylformamide (1 ml) was added dropwise under ice cooling and stirred at the same temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The extracted organic layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate and then filtered to remove the desiccant, followed by distilling off the solvent under reduced pressure to give 6-bromo-1,2,3,4-tetrahydroquinoline (137 mg) as a yellow oil.
Reaction SMILES: [H][H].[CH2:3]([N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][CH3:17])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:18]=O>[Pt]=O.C(O)C>[CH2:3]([N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([N:16]([CH3:18])[CH3:17])[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CNC1CCCN(Cc2ccccc2)C1
Reactant: C=O
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CN(C)C1CCCN(Cc2ccccc2)C1

Procedure:
A suspension of 0.30 g. of platinum oxide in 25 ml. of absolute ethanol was shaken under 35 psi of hydrogen for 1 hour. To this was added a solution of the 1-benzyl-3-methylaminopiperidine and 16 g. of 37 percent aqueous formaldehyde in 40 ml. of ethanol. The mixture was then shaken under ca. 50 psi of hydrogen until uptake ceased. Filtration and evaporation left an oil, which was dissolved in benzene and extracted with dilute hydrochloric acid. The extract was made strongly basic with sodium hydroxide and was extracted with methylene chloride. After drying, the solvent was evaporated, leaving 1-benzyl-3-dimethylaminopiperidine.