Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]1[CH:20]=[CH:19][N:18]2[N:21]=[CH:22][C:23]([NH2:24])=[C:17]2[N:16]=1.C1N=CN([C:31]([N:33]2[CH:37]=N[CH:35]=[CH:34]2)=[O:32])C=1.Cl.N1CC([OH:43])C1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:25][CH:2]([F:1])[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]1[CH:20]=[CH:19][N:18]2[N:21]=[CH:22][C:23]([NH:24][C:31]([N:33]3[CH2:34][CH:35]([OH:43])[CH2:37]3)=[O:32])=[C:17]2[N:16]=1
Reactant: OC1CNC1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3C(F)F)nc12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3C(F)F)nc12)N1CC(O)C1
Reaction time: 2 h

Procedure:
To a DCM (0.6 mL) solution of (R)-5-(2-(2-(difluoromethyl)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (10 mg, 0.028 mmol, prepared as described in the following paragraph), was added CDI (9 mg, 0.056 mmol) at ambient temperature in one portion. After stirring two hours, azetidin-3-ol hydrochloride (6 mg, 0.056 mmol) was added in one portion, followed by addition of DIEA (0.015 mL, 0.084 mmol). The reaction was stirred overnight before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 0 to 50% acetonitrile/water to yield the final product as a solid. MS (apci) m/z=447.2 (M+H).
Reaction SMILES: O=[C:2](Cl)[O:3][C:4](Cl)(Cl)Cl.[C:9]([O:12][C:13]1[CH:24]=[CH:23][C:16]([CH2:17][C@@H:18]([C:20]([OH:22])=[O:21])[NH2:19])=[CH:15][CH:14]=1)(=[O:11])[CH3:10].C>O1CCOCC1>[N-:19]=[C:4]=[O:3].[CH3:2][O:21][C:20](=[O:22])[C@H:18]([CH2:17][C:16]1[CH:23]=[CH:24][C:13]([O:12][C:9](=[O:11])[CH3:10])=[CH:14][CH:15]=1)[NH2:19]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC(=O)Oc1ccc(C[C@H](N)C(=O)O)cc1
Solvent: C1COCCO1
Product: COC(=O)[C@@H](N)Cc1ccc(OC(C)=O)cc1
Product: [N-]=C=O

Procedure:
0.35 mol diphosgene is added dropwise over 1 hour to a mixture of 0.28 mol of the methyl ester of O-acetyltyrosine and 0.4 g activated charcoal in 400 mL dioxane under N2. The reaction mixture is then heated and stirred at reflux for 21/2 hours. The reaction mixture is then cooled, filtered, and concentrated to dryness by rotary evaporator, keeping exposure to moisture to a minimum. The crude product is re-dissolved in 100 mL THF, and the pH of the solution is adjusted to 5.5-6.0 by addition of pyridine. The product mixture is again filtered, and the filtrate fractionally distilled to give O-acetyltyrosine methyl ester isocyanate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]1(=[O:19])[CH2:17][CH2:16][CH2:15][C:14](=O)[CH2:13]1.[CH2:20]([O:22][C:23](=[O:28])[CH2:24][C:25](=[NH:27])[NH2:26])[CH3:21]>>[CH2:20]([O:22][C:23]([C:24]1[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:13]2[C:12](=[O:19])[CH2:17][CH2:16][CH2:15][C:14]=2[NH:26][C:25]=1[NH2:27])=[O:28])[CH3:21]
Reactant: O=C1CCCC(=O)C1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)CC(=N)N
Product: CCOC(=O)C1=C(N)NC2=C(C(=O)CCC2)C1c1cccc([N+](=O)[O-])c1
Yield: 61 %

Procedure:
Upon boiling a solution of 7.6 g of 3-nitrobenzaldehyde, 5.6 g of cyclohexane-1,3-dione and 6.5 g of amidinoacetic acid ethyl ester for 1 hour, 2-amino-4-(3-nitrophenyl)-1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester of melting point >260°C is obtained (alcohol/DMF).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][N:11]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].O.O.[Sn](Cl)Cl>CO>[CH2:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[N:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)[CH2:8][CH2:9]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: C=CCN1CCN(c2ccc(N)cn2)CC1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
2.2 g (8.86 mmol) of 1-allyl-4-(5-nitropyridin-2-yl)piperazine from Example 1.1 were dissolved in 150 ml of methanol after which 18 g (79.75 mmol) of tin(II) chloride dihydrate were added and the mixture was stirred at 70° C. for 4 hours. After the solvent had been evaporated down to dryness, water was added to the residue. The aqueous reaction mixture was made alkaline with dilute sodium hydroxide solution and then extracted with ethyl acetate. The solid which had precipitated out was filtered off. After that, the phases were separated and the aqueous phase was extracted in each case twice with ethyl acetate and dichloromethane. The combined organic phases were dried over sodium sulfate. 1.74 g (90% of theory) of the title compound were obtained after the drying agent had been removed and the solvent had been evaporated down to dryness.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[C:15]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:14][C:13]([CH:20]([CH3:24])[C:21](Cl)=[O:22])=[CH:12][C:11]=1[C:25]([CH3:28])([CH3:27])[CH3:26]>CCCCCCC>[CH2:1]([NH:8][C:21](=[O:22])[CH:20]([C:13]1[CH:14]=[C:15]([C:16]([CH3:17])([CH3:18])[CH3:19])[C:10]([OH:9])=[C:11]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:12]=1)[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C(=O)Cl)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: NCc1ccccc1
Solvent: CCCCCCC
Product: CC(C(=O)NCc1ccccc1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
To a solution of 22.4 g of benzyl amine (0.21 mol) in 100 ml of heptane 29.6 g of 4-hydroxy-3,5-di-tert.-butylphenyl-propionic acid-chloride (0.1 mol) -- dissolved in 200 ml of heptane -- were added dropwise at 20°C, then the solution was boiled under reflux for 3 hours. Working up followed in the manner described in Example 12.
Reaction SMILES: C([O:5][P:6]([O:13][CH2:14][C:15]([NH:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([S:27][C:28]2[CH:33]=[CH:32][C:31]([NH:34]C(=O)OC(C)(C)C)=[CH:30][CH:29]=2)=[C:23]([NH:42][C:43]2[C:44]3[CH:52]=[CH:51][C:50]([CH:53]([CH3:55])[CH3:54])=[N:49][C:45]=3[N:46]=[CH:47][N:48]=2)[CH:22]=1)=[O:20])([CH3:17])[CH3:16])([O:8]C(C)(C)C)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+:67]>ClCCl>[P:6]([O-:7])([O-:8])([O:13][CH2:14][C:15]([NH:18][C:19](=[O:20])[C:21]1[CH:26]=[CH:25][C:24]([S:27][C:28]2[CH:29]=[CH:30][C:31]([NH2:34])=[CH:32][CH:33]=2)=[C:23]([NH:42][C:43]2[C:44]3[CH:52]=[CH:51][C:50]([CH:53]([CH3:54])[CH3:55])=[N:49][C:45]=3[N:46]=[CH:47][N:48]=2)[CH:22]=1)([CH3:17])[CH3:16])=[O:5].[Na+:67].[Na+:67]
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)NC(C)(C)COP(=O)(OC(C)(C)C)OC(C)(C)C)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc2c(Nc3cc(C(=O)NC(C)(C)COP(=O)([O-])[O-])ccc3Sc3ccc(N)cc3)ncnc2n1
Reaction time: 1 h
Yield: 90.7 %

Procedure:
The product of Example 95D (90 mg, 0.11 mmol) in dichloromethane (0.5 mL) was reacted with trifluoroacetic acid [TFA] (0.5 mL) dropwise at room temperature then stirred for 1 hour. The reaction was concentrated and re-dissolved in a mixture of methanol and water to which was added sodium hydrogencarbonate (0.10 g, 1.19 mmol). Purification of the residue on a reverse phase C18 column eluting with a gradient of methanol in water (0-100%) gave the title compound as a yellow solid (62.5 mg, 88%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.29 (d, J=6.99 Hz, 6 H) 1.32 (s, 6 H) 3.03-3.20 (m, 1 H) 3.54 (d, J=11.40 Hz, 2 H) 5.45 (s, 2 H) 6.50-6.53 (m, 1 H) 6.62 (d, J=8.46 Hz, 2 H) 7.11 (d, J=8.46 Hz, 2 H) 7.34 (s, 1 H) 7.60 (s, 1 H) 7.87 (s, 1 H) 8.29 (s, 1 H) 8.74 (s, 1 H) 9.82 (s, 1 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([C:10]([CH3:21])([CH3:20])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:3]=1.[Mg].II.[C:25](=[O:27])=[O:26].Cl>C1COCC1>[CH3:20][C:10]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[O:8][CH3:9])[C:25]([OH:27])=[O:26])([CH3:21])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCC(C)(C)c1cc(Br)ccc1OC
Reactant: O=C=O
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCCCC(C)(C)c1cc(C(=O)O)ccc1OC
Temperature: -40 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
The 4-bromo-2-(1,1-dimethyldecyl) anisole (15.72 g, 44.2 mmoles) obtained in Example 11(a), above, is dissolved in THF (50 ml). This solution is slowly added to magnesium (1.18 g, 48.7 mmoles) and an iodine crystal, while being maintained at reflux by heating. Once the addition is complete, the reaction mixture is maintained at reflux for 30 minutes and then cooled to -40° C. 300 ml of THF are added and a stream of CO2 is passed therethrough for 2 hours. The reaction mixture is then poured into a solution of HCl (4N, 300 ml) and the product is extracted with ether (3×300 ml). The organic phase is washed with water until neutral, dried on MgSO4, and the solvents are evaporated. The residue is pulverized in isooctane to produce 7.25 g (51% yield) of 3-(1,1-dimethyldecyl)-4-methoxy benzoic acid which melts at 112° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][CH2:29][C:30]([O:32]C)=O)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1.[CH3:34][NH2:35]>>[CH3:34][NH:35][C:30](=[O:32])[CH2:29][O:28][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[C:18]([NH:17][C:13]1[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[N:9]=[CH:10]3)=[N:19][CH:20]=[N:21]2
Reactant: COC(=O)COc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Reactant: CN
Product: CNC(=O)COc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Yield: 76 %

Procedure:
Using the same procedure as in Example 5, methyl [(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]acetate (250 mg, 0.55 mmol) was reacted with methylamine to give the title compound as a white solid (185 mg, 76%), except that the residue was purified by chromatography on silica gel (eluant: 5% to 6% methanol in DCM). NMR Spectrum 2.73 (d, 3H), 4.88 (s, 2H), 5.77 (s, 2H), 6.97 (m, 2H), 7.29 (m, 1H), 7.37 (d, 1H), 7.76-7.69 (m, 3H), 7.84 (m, 1H), 8.16 (s, 1H), 8.32 (m, 1H), 8.54 (m, 3H), 10.84 (br s, 1H); Mass spectrum MH+ 440.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16](=[O:20])(=[O:19])[NH:17][CH3:18])=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[F:28][C:29]([F:42])([F:41])[C:30]1[S:34][C:33]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[N:32][N:31]=1>>[CH:1]1([O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16]([NH:17][CH3:18])(=[O:20])=[O:19])=[CH:12][C:8]=2[C:9]([N:38]2[CH2:37][CH2:36][N:35]([C:33]3[S:34][C:30]([C:29]([F:41])([F:28])[F:42])=[N:31][N:32]=3)[CH2:40][CH2:39]2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CNS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)O)c1
Reactant: FC(F)(F)c1nnc(N2CCNCC2)s1
Solvent: O=C(O)C(F)(F)F
Product: CNS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)N2CCN(c3nnc(C(F)(F)F)s3)CC2)c1
Yield: 46 %

Procedure:
Prepared in analogy to example 1 (b) from 2-cyclopentyloxy-5-methylsulfamoyl-benzoic acid (Example A29) and 1-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-piperazine trifluoroacetate (Example 62(b)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to yield the title compound as a white solid (yield 46%). MS (m/e): 520.3 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH2:20][C:21](O)=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19].[NH:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1.C1C=CC2N(O)N=NC=2C=1.O.C(Cl)CCl.Cl>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])[CH2:20][C:21](=[O:22])[N:33]1[CH2:34][CH2:35][CH:30]([C:27]2[CH:26]=[CH:25][N:24]=[CH:29][CH:28]=2)[CH2:31][CH2:32]1
Reactant: c1cc(C2CCNCC2)ccn1
Reactant: COc1ccccc1C1(CC(=O)O)C(=O)Nc2ccc(Cl)cc21
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: COc1ccccc1C1(CC(=O)N2CCC(c3ccncc3)CC2)C(=O)Nc2ccc(Cl)cc21
Reaction time: 0.25 h
Yield: 82.8 %

Procedure:
To a solution of 720 mg of [5-chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]acetic acid, which is the compound described in Preparation 1.1 of the brochure WO03/008407 and 350 mg of 4-piperidin-4-yl pyridine obtained in Step 51-1 in CHCl3 (15 ml) was added 500 mg of HOBt/H2O, stirred for 15 minutes, then, 500 mg of EDC/HCl was added. The solution was stirred for 11 hours, then, water was added and the resulting mixture was extracted with CHCl3. The organic layer was washed with water saturated brine, dried over Na2SO4, then, the drying agent was separated by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (first time: silicagel 60; mobile phase: CHCl3/MeOH=9/1 to 5/1; second time: silica gel NH; mobile phase: CHCl3/MeOH=19/1) to obtain 850 mg of the title compound (colorless amorphous).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12].C([Si]([O:20][C:21]1[CH:26]=[C:25]([F:27])[C:24](B2OC(C)(C)C(C)(C)O2)=[C:23]([F:37])[CH:22]=1)(C)C)(C)(C)C>>[F:27][C:25]1[CH:26]=[C:21]([OH:20])[CH:22]=[C:23]([F:37])[C:24]=1[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12]
Reactant: CC1(C)OB(c2c(F)cc(O[Si](C)(C)C(C)(C)C)cc2F)OC1(C)C
Reactant: COC(=O)c1ccc(F)c(Br)n1
Product: COC(=O)c1ccc(F)c(-c2c(F)cc(O)cc2F)n1
Yield: 65 %

Procedure:
Method 1 was followed using methyl 6-bromo-5-fluoropicolinate (1.0 equiv.) and tert-butyl(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)dimethylsilane (1.75 equiv.) to give methyl 6-(2,6-difluoro-4-hydroxyphenyl)-5-fluoropicolinate in 65% yield. The reaction was heated for an additional 30 minutes at 100° C. in the microwave to drive to completion the deprotection of the TBDMS group. LC/MS=283.9 (M+H), Rt=0.69 min.
Reaction SMILES: [SH:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].FC(F)(F)C(O)=O.[CH3:16][O:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[C:19]=1[CH2:20]O>C(Cl)Cl>[CH3:7][C:2]([S:1][CH2:20][C:19]1[C:22]([O:28][CH3:29])=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:18]=1[O:17][CH3:16])([CH3:8])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CC(C)(S)CC(=O)O
Reactant: COc1cc(OC)c(CO)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(OC)c(CSC(C)(C)CC(=O)O)c(OC)c1
Reaction time: 0.08 h
Yield: 70 %

Procedure:
To a solution of 3-mercapto-3-methylbutyric acid (B. J. Sweetman et al. J. Med Chem., 14, 868 (1971)) (4.6 g, 34 mmol) in methylene chloride (250 mL) under nitrogen and cooled over ice/salt to 5 ûC (internal temperature) was added trifluoroacetic acid (82 g, 0.72 mol). No significant temperature rise was noted during the addition. To this was then added dropwise a solution of 2,4,6-trimethoxybenzyl alcohol (M. C. Munson et al., J. Org. Chem., 57, 3013 (1992)) (6.45 g, 32 mmol) in methylene chloride (150 mL) such that the reaction temperature does not rise above 5 ûC. After the addition was complete, the mixture was stirred for an additional 5 min at 5 ûC and the volatiles were removed in vacuo (toluene or ethyl acetate can be used to assist in the removal of volatile material). The residue was partitioned between diethyl ether and water and the organic phase dried over anhydrous sodium sulfate, filtered and the volatile material removed in vacuo. The residue was treated with activated charcoal and recrystalised from diethyl ether/hexane. The product was isolated as an white solid in 70% yield (7 g) mp 103-105° C. 1H NMR (CDCl3) δ6.12 (s, 2H), 3.80-3.85 (m, 11 H), 2.74 (s, 2H), 1.47 (s, 6H). 13C NMR (CDCl3) δ173.9, 160.6, 158.6, 105.6, 90.5, 55.7, 55.3, 45.9, 43.6, 28.4, 21.0.
Reaction SMILES: OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[CH2:15]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:16]#[CH:17].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][CH2:33][OH:34]>C(#N)C>[CH2:15]([N:18]1[CH2:23][CH2:22][N:21]([CH2:31][CH2:32][CH2:33][OH:34])[CH2:20][CH2:19]1)[C:16]#[CH:17]
Reactant: C#CCN1CCNCC1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: C#CCN1CCN(CCCO)CC1
Temperature: 85 °C
Yield: 78.5 %

Procedure:
1-Prop-2-yn-1-ylpiperazine diTFA salt (704 mg, 2 mmol), (prepared as described for the starting material in Example 26), was dissolved in acetonitrile (5 ml). Potassium carbonate (1.38 g, 10 mmol) and 3-bromopropan-1-ol (180 μL, 2 mmol) were added and the mixture heated to 85° C. for 6.5 hours. The reaction mixture was cooled, filtered and concentrated to give an oil. This was triturated with diethyl ether to give a white solid, which was partitioned between dichloromethane and water. The organic phase was then dried (MgSO4) and concentrated to give 3-(4-prop-2-yn-1-ylpiperazin-1-yl)propan-1-ol (286 mg, 79%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:20]=[CH:19][C:18]2OC3C(=CC=CC=3)NC=2C=1.[NH2:21][CH2:22]CC1CCCN1C.[Cl-].[Al+3].[Cl-].[Cl-].CO>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:20][CH2:19][CH2:18][N:21]1[CH3:22]
Reactant: c1ccc(-c2ccc3c(c2)Nc2ccccc2O3)nc1
Reactant: CN1CCCC1CCN
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Product: CN1CCCC1c1ccccn1
Reaction time: 1 h
Yield: 118.5 %

Procedure:
2-Pyridinyl phenoxazine (46 mg,), 2-(2-aminoethyl)-1-methylpyrrolidine (20 ul, 0.13 mmol) and aluminum chloride (21 mg, 0.1575 mmol) were mixed in anhydrous dichloromethane (1 ml) and stirred for 1 h. The mixture was then evaporated to a residue which was washed with saturated aqueous sodium potassium tartaric acid. The mixture was then extracted with 3×10 ml dichloromethane and the extracts dried (Na2SO4) and evaporated. The compound was then isolated using preparative thin layer chromatography (Al2O3, 3% MeOH in dichloromethane) to yield the 2-pyridinyl methylpyrollidine (25 mg) as a yellow solid.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[NH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11]1>C1COCC1>[C:16]1([C:13]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][NH:7][C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6])[CH2:15][CH2:14]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C=C1CC(=O)O1
Reactant: NCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Reaction time: 1 h
Yield: 87.9 %

Procedure:
Diketene (1.50 mL, 19.2 mmol, 1.50 equiv) was added at 0° C. to a stirred solution of 1-(2-aminoethyl)-4,4-diphenylpiperidine (3.60 g, 12.8 mmol, 1.00 equiv) in anhydrous THF (40 mL) under argon, and stirring was continued at room temperature for 1 hour. The mixture was concentrated to give 4.10 g (88%) of white solid, which was characterized spectroscopically and used for the next reaction without purification.
Reaction SMILES: [CH3:1][O-].[Na+].[CH2:4]([O:6][C:7](=[O:17])[C:8]([CH2:15][CH3:16])(CC)P(O)(O)=O)C.[CH3:18]/[C:19](=C\CC)/[CH:20]=O.O>CO.O1CCCC1>[CH3:1]/[C:16](=[CH:18]\[CH2:19][CH3:20])/[CH:15]=[CH:8]/[C:7]([O:6][CH3:4])=[O:17]
Reactant: C[O-]
Reactant: CC/C=C(\C)C=O
Reactant: CCOC(=O)C(CC)(CC)P(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC/C=C(C)/C=C/C(=O)OC
Reaction time: 0.5 h

Procedure:
To a 28 wt % solution of sodium methoxide in methanol (226 g) at 20° C. was added dropwise diethyl phosphonoacetic acid ethyl ester (239.8 g). The solution was stirred at the same temperature for 30 minutes under a nitrogen atmosphere. A solution of (E)-2-methyl-2-pentenal (100 g) in tetrahydrofuran (200 ml) was added dropwise at 20° C. during 20 minutes and the solution was stirred for 1 hour. The reaction mixture was poured into chilled water and extracted twice with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give methyl (E,E)-4-methyl-2,4-heptadienoate (169.2 g) as an oil. This oil was used in the next reaction without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.CO[CH2:12][CH2:13][O:14][CH3:15].[C:16](=[O:19])([O-])[O-:17].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH3:15][O:14][C:13]1[CH:12]=[C:2]([CH:3]=[CH:4][C:5]=1[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[C:16]([OH:17])=[O:19]
Reactant: OB(O)c1ccncc1
Reactant: COCCOC
Reactant: O=C([O-])[O-]
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: COc1cc(C(=O)O)ccc1-c1ccncc1
Temperature: 25 °C

Procedure:
Intermediate 38 (1.06 g), 4-pyridinylboronic acid (486 mg), DME (25 ml), 2N sodium carbonate (10 ml) and tetrakis(triphenylphosphine) palladium (0) (70 mg), were heated to reflux for 18 h under nitrogen. After allowing to cool to room temperature, water (50 ml) was added and the mixture was washed with ethyl acetate (2×50 ml). The aqueous phase was neutralised with 2N hydrochloric acid, and then concentrated in vacuo onto silica (Merck 9385). Purification by FCC eluting with ethyl acetate:hexane:acetic acid (750:240:10) gave a pale orange solid which was triturated in ether and dried under high vacuum to give the title compound as a pale orange solid (370 mg) m.p. 239°-241° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[N:12]1[CH:17]=[C:16]([C:18]2[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=2)[NH2:21])[CH:15]=[N:14][CH:13]=1>>[N:12]1[CH:17]=[C:16]([C:18]2[CH:19]=[C:20]([NH:21][C:2]3[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=3[N+:9]([O-:11])=[O:10])[CH:22]=[CH:23][CH:24]=2)[CH:15]=[N:14][CH:13]=1
Reactant: O=[N+]([O-])c1cc(I)ccc1F
Reactant: Nc1cccc(-c2cncnc2)c1
Product: O=[N+]([O-])c1cc(I)ccc1Nc1cccc(-c2cncnc2)c1
Yield: 79 %

Procedure:
N-(3-(5-Pyrimidyl)phenyl)-4-iodo-2-nitroaniline (6b) was prepared analogously from 1c (Example 1) and 2b (Example 2). Yield 79%. Mp 214-217° C.