Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].CCN(CC)CC.[Br:20][CH2:21][C:22]1[C:23]([CH2:28]Br)=[CH:24][CH:25]=[CH:26][CH:27]=1>CN(C=O)C>[Br:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][O:1][N:2]1[C:3](=[O:12])[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:7]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: BrCc1ccccc1CBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1OCc1ccccc1CBr
Temperature: 25 °C
Reaction time: 4 h
Yield: 45.6 %

Procedure:
To a stirred solution of N-hydroxyphthalimide (0.60 g, 3.68 mmol) and Et3N (0.60 mL, 4.30 mmol) in DMF (6 mL) was added α,α′-dibromo-o-xylene (3.30 g, 0.0125 mol) and the mixture stirred at room temperature for 4 h. The resultant brown precipitate was filtered and washed with CH2Cl2. The filtrate was diluted with EtOAc (40 mL) and water (30 mL) and the organic phase washed with brine (1×30 mL), dried (Na2SO4) and concentrated under reduced pressure. The resultant yellow oil was purified by column chromatography on silica gel (4:1 Hexanes/EtOAc) to give the title compound (581 mg, 46%) as a white solid. 1H NMR (CDCl3) δ4.99 (s, 2H), 5.37 (s, 2H), 7.27-7.40 (m, 2H), 7.41-7.45 (m, 2H), 7.73-7.76 (m, 2H), 7.81-7.84 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1([C:15]([NH2:17])=[O:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.CO[C:20](OC)(OC)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[O:16]=[C:15]1[C:2]2([CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][CH2:3]2)[N:1]=[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C(N)=O)CC1
Reactant: COC(OC)(OC)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)N=C(c1ccccc1)NC2=O
Yield: 30.8 %

Procedure:
A solution of tert-butyl 4-amino-4-(aminocarbonyl)piperidine-1-carboxylate (120 mg, 0.493 mmol) and trimethyl orthobenzoate (198 mg, 1.09 mmol) in toluene (7 mL) was heated at 110° C. for 18 h. The reaction was concentrated and the crude product was purified by silica gel chromatography, eluting with a gradient of 0 to 5% methanol:dichloromethane to give the title compound (50 mg). MS: m/z=330.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([C:13]([CH3:50])([CH3:49])[C:14]([N:16]([CH3:48])[C:17]2[C:18]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=3[CH3:47])=[CH:19][C:20]([C@@H:23]3[N:27](C(OC(C)(C)C)=O)[C@@:26]([CH3:39])([C:35]([O:37][CH3:38])=[O:36])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(O)(C(F)(F)F)=O>ClCCl>[F:52][C:2]([F:1])([F:51])[C:3]1[CH:4]=[C:5]([C:13]([CH3:49])([CH3:50])[C:14]([N:16]([CH3:48])[C:17]2[C:18]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=3[CH3:47])=[CH:19][C:20]([C@@H:23]3[NH:27][C@@:26]([CH3:39])([C:35]([O:37][CH3:38])=[O:36])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1
Reactant: COC(=O)[C@@]1(C)CC[C@H](c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)N1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@]1(C)CC[C@H](c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a solution of 1-(1,1-dimethylethyl) 2-methyl (2R,5R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-1,2-pyrrolidinedicarboxylate (Intermediate 7, 30 mg, 0.041 mmol) in dry Dichloromethane (2 ml) was added TFA (0.6 ml, 7.79 mmol) and the reaction mixture was stirred for 2 hours at r.t. The solvent and the excess of TFA were evaporated and the residue was purified by SPE-SCX cartridge affording the title compound (25 mg, 0.039 mmol, 96% yield) as a white solid. HPLC: Rt 5.68 min. MS: m/z 640 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:22]2[CH2:21][CH2:20][N:19]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:24][CH2:23]2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1F
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)cc2[N+](=O)[O-])CC1
Yield: 95 %

Procedure:
Method 1 was followed using 1 eq each of 4-chloro-1-fluoro-2-nitrobenzene, 1-Boc-piperazine, and TEA yielding tert-butyl 4-(4-chloro-2-nitrophenyl)piperazine-1-carboxylate (95%). LCMS (m/z): 342.0 (MH+); LC Rt=3.50 min.
Reaction SMILES: [CH3:1][NH2:2].CO.[Cl:5][C:6]1[S:7][C:8]([S:12](Cl)(=[O:14])=[O:13])=[C:9]([CH3:11])[N:10]=1.O>ClCCl>[Cl:5][C:6]1[S:7][C:8]([S:12]([NH:2][CH3:1])(=[O:14])=[O:13])=[C:9]([CH3:11])[N:10]=1
Reactant: CN
Reactant: Cc1nc(Cl)sc1S(=O)(=O)Cl
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CNS(=O)(=O)c1sc(Cl)nc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
177 ml of a solution of methylamine in methanol (2 M, 0.354 mol) are added at 0° C. to a solution of 41 g (0.177 mol) of 2-chloro-4-methyl-1,3-thiazole-5-sulphonyl chloride in 360 ml of dichloromethane. The mixture is stirred at 0° C. for 30 min, 1.8 l of water are added, and the mixture is extracted 5 times with 400 ml of dichloromethane each time. The combined organic phases are dried over sodium sulphate, and the solvent is distilled off. 39.93 g of an oil, which solidifies on standing, are obtained (Rf=0.43 (toluene/ethyl acetate=2/1), yield 99.7%)
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:3]1.[CH3:13][I:14]>>[I-:14].[CH3:13][N+:8]1([CH:4]2[CH2:5][CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3]2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC1CCCC(N2CCCC2)C1
Reactant: CI
Product: CC1CCCC([N+]2(C)CCCC2)C1
Product: [I-]
Yield: 94 %

Procedure:
N-(3-methylcyclohexyl)pyrrolidine prepared in example 2 above was quaternized with methyl iodide in a similar fashion to the procedure described in example 4. The quaternization afforded the desired N-methyl-N-(3-methylcyclohexyl)pyrrolidinium iodide in 94% yield. The resulting iodide salt was exchanged with Bio-Rad AG 1-X8 ion-exchange resin as described in example 4 to give N-methyl-N-(3-methylcyclohexyl)pyrrolidinium hydroxide in 98% yield (titration analysis).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C>[Br-:1].[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1ccc(Br)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [Br-]
Product: c1ccc(COc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 4-bromophenol (40 mmol), benzylbromide (40 mmol) and Na2CO3 in DMF (200 mL) was stirred at room temperature for 24 hours and was then poured into water. A solid was collected and was further recrystallized from hexane to give 4-benzyloxybenzene bromide in almost quantitative yield. A solution of the bromide in THF (100 mL) was treated with BuLi (44 mmol) at -78° C. over 30 minutes and then with a solution of ZnI2 (40 mmol) in THF (40 mL) over 20 minutes. After the resulting mixture was warmed to room temperature over an hour, it was cooled to -78° C. and a solution of copper (I) cyanide (40 mmol) and lithium chloride (80 mmol) in THF (50 mL) was slowly added. The resulting mixture was warmed and stirred at -20° C. for 20 minutes, cooled to -78° C., and to it was added ethyl 2-(bromomethyl)acrylate (40 mmol). The resulting mixture was stirred at -78° C. for 2 hours and was then warmed to room temperature overnight. Ether and aqueous saturated ammonium chloride were added and filtered. The filtrate was washed with water and brine, and dried over MgSO4. Concentration gave a residue, which was purified by column chromatography with gradient solvent system (CH2Cl2 -EtOAc) to give the title compound (3.6 g, 30.4%): 1H NMP (CDCl3) δ7.44-7.26 (m, 5H),7.12 (d, J=8.4 Hz, 2H), 6.91 (d, J=8.4 Hz, 2H), 6.20 (s, 1H), 5.92 (s, 1H), 5.07 (s, 2H), 4.18 (q, J=7.4 Hz, 2H), 3.57 (s, 2H), 1.27 (t, J=7.4 Hz, 3H); MS: 314 (M+NH4)+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]([C:15]2([C:18]3[CH:28]=[CH:27][C:21]4[O:22][C:23]([F:26])([F:25])[O:24][C:20]=4[CH:19]=3)[CH2:17][CH2:16]2)=[O:14])[N:3]=1.CC1(C)C(C)(C)OC([C:37]2[CH:45]=[C:44]3[C:40]([CH2:41][NH:42][C:43]3=[O:46])=[CH:39][CH:38]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:25][C:23]1([F:26])[O:22][C:21]2[CH:27]=[CH:28][C:18]([C:15]3([C:13]([NH:12][C:4]4[N:3]=[C:2]([C:37]5[CH:45]=[C:44]6[C:40](=[CH:39][CH:38]=5)[CH2:41][NH:42][C:43]6=[O:46])[C:11]5[C:6]([CH:5]=4)=[CH:7][CH:8]=[CH:9][CH:10]=5)=[O:14])[CH2:17][CH2:16]3)=[CH:19][C:20]=2[O:24]1
Reactant: CC1(C)OC(c2ccc3c(c2)C(=O)NC3)OC1(C)C
Reactant: O=C(Nc1cc2ccccc2c(Br)n1)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C1NCc2ccc(-c3nc(NC(=O)C4(c5ccc6c(c5)OC(F)(F)O6)CC4)cc4ccccc34)cc21
Temperature: 120 °C

Procedure:
N-(1-Bromoisoquinolin-3-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (45 mg, 0.10 mmol) was dissolved in 1 mL of 1,2-dimethoxyethane in a reaction tube. 6-(4,4,5,5-Tetramethyl-1,3-dioxolan-2-yl)isoindolin-1-one (38 mg, 0.15 mmol), 0.1 mL of an aqueous 2 M sodium carbonate solution, and tetrakis(triphenylphosphine)palladium(0) (6.0 mg, 0.0050 mmol) were added and the reaction mixture was heated at 120° C. for ten minutes under microwave irradiation. The reaction mixture was evaporated to dryness and the residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate/hexanes. ESI-MS m/z calc. 499.5. found 500.3 (M+1)+. Retention time 1.93 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.N1C=CC=CC=1.[Cl:27][C:28]1[N:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>C1COCC1>[Cl:19][C:6]1[CH:5]=[C:4]([NH:20][S:34]([C:31]2[CH:32]=[N:33][C:28]([Cl:27])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: Nc1cc(Cl)c(Sc2ccc3ccccc3c2)c(Cl)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cc(Cl)c(Sc2ccc3ccccc3c2)c(Cl)c1)c1ccc(Cl)nc1
Yield: 55.8 %

Procedure:
The title compound was prepared using the method of example 94, starting with 3,5-dichloro-4-(naphthalen-2-ylsulfanyl)-phenylamine (90) (150 mg, 0.47 mmol), pyridine (Aldrich, 0.19 mL, 2.34 mmol) and 6-chloro-pyridine-3-sulfonyl chloride (Qorpark, 109 mg, 0.52 mmol) in THF. 130 mg (56%) of 96 was obtained as a pale yellow solid.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:14])[CH2:4][NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13].[CH3:15]N(C)C=O.[Cl:20][CH2:21][C:22](Cl)=[O:23].Cl>ClC1C=CC=CC=1>[CH3:1][N:2]([CH3:15])[C:3](=[O:14])[CH2:4][N:5]([C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])[C:22](=[O:23])[CH2:21][Cl:20]
Reactant: CNC(=O)CNc1c(C)cccc1C
Reactant: CN(C)C=O
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: Clc1ccccc1
Product: Cc1cccc(C)c1N(CC(=O)N(C)C)C(=O)CCl
Temperature: 110 °C

Procedure:
31.4 g of 2,6-dimethylanilinoacetic acid methyl amide are dissolved in 250 ml of chlorobenzene. 1.5 ml of dimethyl formamide are added to this solution and the mixture is heated to 110° C. At this temperature 14.3 ml of chloroacetyl chloride are added dropwise with stirring. After 1 1/2 hours the evolution of HCl has virtually ceased. The reaction mixture is allowed to cool and concentrated in a rotary evaporator to leave as residue a blackish-brown oil which is crystallised from ethyl acetate with the addition of animal charcoal. Yield: 22.4 g of N-methyl-[N'-(2,6-dimethylphenyl)-N'-chloroacetylamino]-acetamide (m.p. 140° C-142° C). N,N-dimethyl-(N'-(2,6-dimethylphenyl)-N'-chloroacetylamino]-acetamide was obtained in analogous manner; m.p. 74°-76° C (from ether).
Reaction SMILES: [OH-].[Na+].[I:3][C:4]1[CH:15]=[CH:14][C:7]2[C:8](=[O:13])[O:9][C:10](=O)[NH:11][C:6]=2[CH:5]=1.O>CO>[NH2:11][C:6]1[CH:5]=[C:4]([I:3])[CH:15]=[CH:14][C:7]=1[C:8]([O:9][CH3:10])=[O:13]
Reactant: O=c1[nH]c2cc(I)ccc2c(=O)o1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(I)cc1N
Temperature: 60 °C
Yield: 80.2 %

Procedure:
To a stirred solution of sodium hydroxide (0.048 g, 1.2 mM) in methanol (4.5 mL) was added 7-iodo-2H-3,1-benzoxazine-2,4(1H)-dione (2.6 g, 9.0 mM). The mixture was heated at 60° C. for 7 hr and the resulting solution was cooled, poured into water and extracted with ethyl acetate. The combined extracts were washed once with dilute sodium hydroxide, dried (MgSO4), filtered and concentrated to leave the title compound (2.0 g, 80%) as a brown oil which slowly crystallized; MS(CI): 278 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=[O:10])=[C:7]([N+:12]([O-])=O)[CH:6]=[CH:5][CH:4]=1>C(O)C.[Pd]>[NH2:12][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[C:9]([OH:11])=[O:10]
Reactant: COc1cccc([N+](=O)[O-])c1C(=O)O
Agent: [Pd]
Solvent: CCO
Product: COc1cccc(N)c1C(=O)O
Yield: 100.2 %

Procedure:
A solution of 6-methoxy-2-nitrobenzoic acid (3.25 g, 16.5 mM) in ethanol (180 mL) containing 10% palladium-on-carbon catalyst (0.30 g) was hydrogenated using a Parr apparatus. When hydrogen consumption ceased, the resulting mixture was filtered through diatomaceous earth and the filtrate concentrated to provide the title benzoic acid (2.76 g, 100%) as a tan solid; MS(CI): 168 (M+H).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH:19]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([O:31][CH3:32])[CH:22]=1)=O.[F:33][C:34]([F:51])([F:50])[CH2:35]P(=O)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[F:33][C:34]([F:51])([F:50])/[CH:35]=[CH:19]/[C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([O:31][CH3:32])[CH:22]=1
Reactant: O=P(CC(F)(F)F)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(/C=C/C(F)(F)F)cc1OC
Reaction time: 8 h

Procedure:
MS 4 Å (powder, 16 g) was added to a 1 M solution of TBAF in THF (20 mL, 20 mmol), and the mixture was stirred at room-temperature overnight under an argon atmosphere. To the mixture were added a solution of methyl 4-formyl-2-methoxybenzoate (420 mg, 0.0022 mol) and 2,2,2-trifluoroethyldiphenylphosphine oxide (1.23 g, 0.00432 mol) in THF (20 mL). After the mixture was stirred for 2 h, MS 4 Å was removed by filtration. The filtrate was concentrated and water (120 mL) was added. The mixture was extracted with AcOEt. The extract was washed with brine, dried (Na2SO4), and concentrated. The residue was purified by column chromatography on silica gel using AcOEt-hexane (0-15%) as eluent to give (E)-methyl 4-(3,3,3-trifluoroprop-1-enyl)-2-methoxybenzoate as a white solid, followed by (Z)-methyl 4-(3,3,3-trifluoroprop-1-enyl)-2-methoxybenzoate as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[C:5]([NH:7][C:8]1[C:9]([N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][C:23](O)=[O:24])[CH2:18][CH2:17]2)=[N:10][CH:11]=[C:12]([C:14]#[N:15])[CH:13]=1)=[O:6].[OH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[C:5]([NH:7][C:8]1[C:9]([N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][C:23]([N:33]3[CH2:34][CH2:35][CH:30]([OH:29])[CH2:31][CH2:32]3)=[O:24])[CH2:18][CH2:17]2)=[N:10][CH:11]=[C:12]([C:14]#[N:15])[CH:13]=1)=[O:6]
Reactant: OC1CCNCC1
Reactant: N#Cc1cnc(N2CCC(CC(=O)O)CC2)c(NC(=O)c2cccc(Cl)c2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1cnc(N2CCC(CC(=O)N3CCC(O)CC3)CC2)c(NC(=O)c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
A mixture of 0.015 g (0.038 mmol) of [3′-(3-chloro-benzoylamino)-5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid, 0.019 g (0.19 mmol) of 4-hydroxypiperdine, 0.016 g (0.049 mmol) of 0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, and 0.016 mL (0.11 mmol) of triethylamine in N,N-dimethylformamide (2 mL) is allowed to stir at room temperature overnight. The mixture is concentrated under reduced pressure and the residue is diluted with water which results in a solid precipitating. The light red solid is collected by filtration and washed with water. The collected material is purified using preparative reverse phase HPLC to give 0.011 g (61%) of the title compound (145) as a colorless solid. [M+H]+=482.2
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:21]=[C:22](CO)[S:23][CH:24]=1)=[CH:16][CH:15]=3.[H-].[Na+].C1(Br)CC1.O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:21]=[CH:22][S:23][CH:24]=1)=[CH:16][CH:15]=3
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4csc(CO)n4)ccc3n(C)c21
Agent: BrC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4cscn4)ccc3n(C)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
150 mg (0.3 mmol) of compound 3-(2,4-dichlorophenyl)-6-[2-(hydroxymethyl)-1,3-thiazol-4-yl]-1,9-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one from Example 9 above are dissolved in 10 ml of DMF. 50 mg of 60% NaH (0.96 mmol) are added and the mixture is stirred at ambient temperature for 30 min. 0.05 ml (0.6 mmol) of cyclopropyl bromide are added and the mixture is then stirred at ambient temperature for 3 hours. Water is added and the mixture is extracted with EtOAc. The product is washed with a saturated NaCl solution followed by adsorption onto silica. Purification is carried out by chromatography on a silica column, elution being carried out with EtOAc.
Reaction SMILES: Cl.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.C([O-])([O-])=[O:19].[K+].[K+].Cl[CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH:36]=O)=[CH:31][C:30]=1[O:38][CH3:39].CN(C)C=O>O>[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:25][CH2:26][CH2:27][O:28][C:29]4[CH:34]=[CH:33][C:32]([C:35](=[O:19])[CH3:36])=[CH:31][C:30]=4[O:38][CH3:39])[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: COc1cc(CC=O)ccc1OCCCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 90 °C
Yield: 58.6 %

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)1,2 benzisoxazole hydrochloride (5.1 g, 20 mmol), K2CO3 (5.2 g, 40 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]2 ethanone (5.3 g, 22 mmol), and dimethylformamide (60 ml) was heated at 90° C. for 16 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was washed (water), dried (MgSO4) and concentrated to afford a moist solid. Recrystallization (twice) from ethyl alcohol afforded 5.0 g (58%) of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-piperidinyl]propoxy]-3-methoxyphenyl]-ethanone as a beige solid, m.p.=118-120° C.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:16][CH2:17]O)[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([CH3:14])=[C:7]([OH:13])[C:8]=2[CH3:12])[O:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:39]>>[CH3:1][C@@:2]1([CH2:16][CH2:17][Cl:39])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([CH3:14])=[C:7]([OH:13])[C:8]=2[CH3:12])[O:3]1
Reactant: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCO)O2
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCCl)O2
Yield: 79.2 %

Procedure:
A mixture of 2 g of (S)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-hydroxyethyl)-chroman, 8 g of carbon tetrachloride and 2.6 g of triphenylphosphine was refluxed for 3 hours, after which the reaction mixture was allowed to cool, the precipitate formed was filtered off under suction and the filtrate was chromatographed over silica gel, using a 5:1 hexane/acetone solvent mixture. 1.7 g of (S)-2,5,7,8-tetramethyl-6-hydroxy-2-(2-chloroethyl)-chroman were obtained. [α]D20 =-9.1° (c=2, chloroform), mp.=111° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[S:20][C:19]2[C:18]([NH:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[NH:27][CH:26]=[CH:25]4)=[N:17][CH:16]=[N:15][C:14]=2[CH:13]=1>>[NH:27]1[C:28]2[C:24](=[CH:23][C:22]([NH:21][C:18]3[C:19]4[S:20][C:12]([C:5]5[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=5)=[CH:13][C:14]=4[N:15]=[CH:16][N:17]=3)=[CH:30][CH:29]=2)[CH:25]=[CH:26]1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Brc1cc2ncnc(Nc3ccc4[nH]ccc4c3)c2s1
Product: Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from p-methylbenzeneboronic acid and (6-bromo-thieno[3,2-d]pyrimidin-4-yl)-(1H-indol-5-yl)-amine by a procedure analogous to example 2. 1H NMR (400 MHz, DMSO) d 11.1 (s, 1H), 9.50 (s, 1H), 8.41 (s, 1H), 7.71 (d, 2H), 7.59 (s, 2H), 7.24 (m, 5H), 6.38 (s, 1H), 2.28 (s, 3H). M.P. 200-220° C.; LC-MS: 357 (MH+); HPLC RT: 4.57 minutes.
Reaction SMILES: [CH2:1]([I:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH3:11][N:12]([CH:14](O)[CH2:15][CH3:16])[CH3:13].CC[O:20]CC>C(#N)C>[I-:10].[OH:20][CH2:16][CH2:15][CH2:14][N+:12]([CH3:13])([CH3:11])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCOCC
Reactant: CCC(O)N(C)C
Reactant: CCCCCCCCCI
Solvent: CC#N
Product: CCCCCCCCC[N+](C)(C)CCCO
Product: [I-]
Yield: 77 %

Procedure:
Employing the procedure of EXAMPLE II, 20.0 g of nonyl iodide was reacted with 14.3 ml of N,N-dimethylaminopropanol in 50 ml of acetonitrile to provide a crude product which was slurried with ether to give 27 g (77%) of an amber oil which solidified on standing. Proton NMR confirmed the desired structure.
Reaction SMILES: [CH3:1][C:2]([CH:7]=[CH:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])=[CH:3][C:4]([OH:6])=O.[CH3:18][CH2:19]OCC.C([Li])C.Cl>C1C=CC=CC=1>[CH3:1][C:2]([CH:7]=[CH:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])=[CH:3][C:4](=[O:6])[CH2:18][CH3:19]
Reactant: CC(C)=CCCC(C)CC=CC(C)=CC(=O)O
Reactant: CCOCC
Agent: Cl
Agent: [Li]CC
Solvent: c1ccccc1
Product: CCC(=O)C=C(C)C=CCC(C)CCC=C(C)C
Reaction time: 3 h

Procedure:
To a stirred solution of 2.4 g. of 3,7,11-trimethyldodeca-2,4,10-trienoic acid in 20 ml. of dry ether is added slowly, at 0°, 23 ml. of a one molar solution of ethyl lithium in benzene. After about 3 hours at 20°, the mixture is poured into iced 1N hydrochloric acid (100 ml.) with vigorous stirring. The ether layer is separated, combined with ethereal washings of the aqueous phase, washed with water, saturated potassium bicarbonate and then saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to yield 5,9,13-trimethyltetradeca-4,6,12-trien-3-one, which can be purified by chromatography.