Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:13](=[O:15])[N:11]([CH3:12])[C:10](=[O:16])[N:9]([CH3:17])[C:8]=2[N:7]=[CH:6]1.[C-:18]#[N:19].[Na+].[I-].[Na+]>CN(C)C=O>[N:11]1([C:13](=[O:15])[C:14]2[N:5]([CH2:4][CH2:3][CH2:2][C:18]#[N:19])[CH:6]=[N:7][C:8]=2[N:9]([CH3:17])[C:10]1=[O:16])[CH3:12]
Reactant: Cn1c(=O)c2c(ncn2CCCCl)n(C)c1=O
Reactant: [C-]#N
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ncn2CCCC#N)n(C)c1=O
Yield: 88 %

Procedure:
57.9 g. of 7-(3-chloro-propan-1-yl)-theophylline, 12.29 g. of sodium cyanide, 2.0 g. of sodium iodide and 400 cm3 of dimethylformamide are stirred at 90° C. for 3 hours. 49.1 g. (88% yield) of γ-(theophylline-7-yl)-butyronitrile are obtained. M.p.: 146°-150° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:5][CH:4]=1.[CH3:13][O:14][C:15](=[O:21])[CH2:16][C:17]([O:19][CH3:20])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:13][O:14][C:15](=[O:21])[CH:16]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:5][CH:4]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: CC(C)Oc1ccc(CCl)cc1
Reactant: COC(=O)CC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(OC(C)C)cc1)C(=O)OC

Procedure:
1-(Chloromethyl)-4-(1-methylethoxy)benzene (20.5 g, 111 mmol), malonic acid dimethyl ester (102.5 g, 776 mmol) and potassium carbonate (46.5 g, 332 mmol, anhydrous, freshly ground) are stirred in absolute DMF (250 ml) for 24 hours at 70° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([N:8]1[C@H:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[CH2:11][O:10][C:9]1=[O:21])=[O:7].[CH3:22][CH:23]([CH3:39])[C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:28]=1)=[O:25]>>[F:20][C:15]1[CH:14]=[C:13]([C@@H:12]2[CH2:11][O:10][C:9](=[O:21])[N:8]2[C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:36]2[CH2:37][CH2:38][CH:33]([C:29]3[CH:28]=[C:27]([NH:26][C:24](=[O:25])[CH:23]([CH3:22])[CH3:39])[CH:32]=[CH:31][CH:30]=3)[CH2:34][CH2:35]2)[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCl)N1C(=O)OC[C@H]1c1ccc(F)c(F)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)N3C(=O)OC[C@H]3c3ccc(F)c(F)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using (4R)-3-(5-chloropentanoyl)-4-(3,4-difluorophenyl)-1,3-oxazolidin-2-one and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 528.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([CH3:27])=[CH:21][C:22](=[O:26])[O:23]2)=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Br-].[OH-:29].[K+].Cl>O.C(O)C.C(Cl)Cl>[CH3:27][C:20]1[C:19]2[CH:18]=[CH:17][C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:25][C:24]=2[O:23][C:21]=1[C:22]([OH:26])=[O:29]
Reactant: CCCCCCCCCCCCCCOc1ccc2c(C)cc(=O)oc2c1
Reactant: [OH-]
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCOc1ccc2c(C)c(C(=O)O)oc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
10.9 g (0.0292 mole) of 7-tetradecyloxy-4-methyl-coumarin and 250 ml of dry methylene chloride is stirred at room temperature. 4.68 g (0.0292 mole) of bromide and 100.0 ml of dry methylene chloride are added over a period of 20 minutes. The mixture is stirred at room temperature for 1 hour and refluxed for 15 minutes. The mixture is then cooled and extracted with 10% Na2SO3. It is washed with a saline solution, dried (Na2SO4) and evaporated to dryness. The product obtained is stirred into a cold solution of 60 g KOH and 150 ml of ethanol. The mixture is heated to reflux for 2 hours and then is diluted with water. After refluxing is continued for about 10 minutes, it is poured into 1 liter of water, acidified with concentrated HCl and extracted with diethyl ether. The ether layer is washed with water and saline solution, dried (Na2SO4) and evaporated with replacement of the solvent with a total volume of 150 ml of hexane. The mixture is allowed to stand at room temperature. The product is collected and dried, yielding 10.4 g (92%) of 3-methyl-6-tetradecyloxybenzofuran-2-carboxylic acid, m.p. 108°-110° C. The mother liquor is concentrated to about 50 ml and cooled, yielding an additional 0.4 g of the 3-methyl-6-tetradecyloxy-benzofuran-2-carboxylic acid, m.p. 105°-108° C. (Overall yield -- 96%.)
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].C([N:20]1[CH2:25][CH2:24][C:23]([NH:32][C:33](OC)=O)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:22][CH2:21]1)C1C=CC=CC=1.[OH-].[Na+].S(=O)(=O)(O)O.[C:44]([OH:49])(=[O:48])[C:45]([OH:47])=[O:46]>C1(C)C=CC=CC=1.C(O)C.[Pd].[O-]S([O-])(=O)=O.[Ba+2].C(O)=O.O>[C:44]([OH:49])(=[O:48])[C:45]([OH:47])=[O:46].[C:44]([OH:49])(=[O:48])[C:45]([OH:47])=[O:46].[CH3:33][NH:32][C:23]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:22][CH2:21][NH:20][CH2:25][CH2:24]1
Reactant: COC(=O)NC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: COCCO[AlH2-]OCCOC
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: O
Solvent: O=CO
Product: CNC1(c2ccccc2)CCNCC1
Temperature: 98 °C
Yield: 85.8 %

Procedure:
2.89 l of toluene are added to a solution of 5.54 kg of Vitride® at 70% in toluene, and the mixture is heated to 98° C. A solution, heated to 80° C., of 2.86 kg of 1-benzyl-4-methoxycarbonylamino-4-phenylpiperidine, obtained in step (a) in 1.3 l of toluene, is added to this solution over 3 hours at 98-100° C. with stirring. 3.92 l of a 5% sodium hydroxide solution are then added at 80° C. The mixture is allowed to cool to 55° C. and the organic phase is separated out by settling at this temperature and washed with water. By extracting the toluene phase with 823 g of formic acid in 8.64 l of water, 11.77 kg of a solution of 1-benzyl-4-methylamino-4-phenylpiperidine formate at pH 5.5 are obtained, and this solution is added to a mixture of 155.2 g of 5% Pd/BaSO4 and 1.35 l of demineralized water preheated to 85° C., with stirring. 96.2 g of 5% of Pd/BaSO4 and 417.4 g of formic acid are gradually added, still at 85° C. The mixture is heated for 12 hours at 85° C. and then allowed to cool to room temperature and 898.5 g of 95% sulfuric acid are added. The mixture is filtered and concentrated under vacuum down to about 6.5 l, 6.5 l of 4-methyl-2-pentanone are then added and the pH of the mixture is brought to 14 by addition of 30% sodium hydroxide. The aqueous phase is separated out by settling of the phases and re-extracted with 4-methyl-2-pentanone, and the combined organic phases are dried via azeotropic distillation. The solution thus obtained is poured into a solution of 1.57 kg of oxalic acid in 13.3 l of absolute ethanol and the precipitate thus obtained is filtered off, washed with ethanol and dried under vacuum at 70° C. 2.77 kg of 4-methylamino-4-phenylpiperidine dioxalate are thus obtained; m.p.=214-215° C. Overall yield calculated from the starting 1-benzyl-4-cyano-4-phenylpiperidine hydrochloride: 78.5% of the theoretical amount.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4](=O)[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][C:9]([CH2:15][CH3:16])([CH3:14])[CH2:8]2.C1([NH3+])CCCCC1>>[CH2:15]([C:9]1([CH3:14])[CH2:8][C:7]2[C:11](=[CH:12][CH:13]=[C:5]([CH2:4][C:3]([OH:18])=[O:2])[CH:6]=2)[CH2:10]1)[CH3:16]
Reactant: CCC1(C)Cc2ccc(C(=O)C(=O)OC)cc2C1
Agent: [NH3+]C1CCCCC1
Product: CCC1(C)Cc2ccc(CC(=O)O)cc2C1

Procedure:
2-ethyl-α-oxo-2-methyl-5-indanacetic acid methyl ester is reduced in a manner analogous to that described in Example 4. The cyclohexyl ammonium salt of the title compound has an M.P. of 149°-151°. The sodium salt of the title compound has an M.P. of 184°-188°.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[C:7]2=[O:16])[CH2:3][CH2:2]1.C(N1C2C(=CC=CC=2)C(=O)C1=O)CCCC.O1C2C=CC(O)=CC=2OC1.[O:43]1[C:47]2[CH:48]=[C:49]([OH:52])[CH:50]=[CH:51][C:46]=2[CH2:45][CH2:44]1>>[OH:15][C:8]1([C:50]2[C:49]([OH:52])=[CH:48][C:47]3[O:43][CH2:44][CH2:45][C:46]=3[CH:51]=2)[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]([CH2:5][CH2:4][CH2:1][CH2:3][CH3:2])[C:7]1=[O:16]
Reactant: Oc1ccc2c(c1)OCC2
Reactant: O=C1C(=O)N(CCC2CC2)c2ccccc21
Agent: CCCCCN1C(=O)C(=O)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: CCCCCN1C(=O)C(O)(c2cc3c(cc2O)OCC3)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 2B, and making non-critical variations to replace 1-(2-cyclopropylethyl)-1H-indole-2,3-dione with 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with 2,3-dihydrobenzofuran-6-ol, the title compound was obtained (90%) as a white powder: MS (ES+) m/z 376.3 (M+23).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].O.[NH2:6][CH:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8]1.C(=O)([O-])[O-].[Ca+2]>ClC(Cl)Cl>[N:6]([CH:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8]1)=[C:1]=[S:2]
Reactant: S=C(Cl)Cl
Reactant: CCOC(=O)N1CCC(N)C1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)N1CCC(N=C=S)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.3 %

Procedure:
(a-1) To a stirred mixture of 25 parts of carbonothioic dichloride, 65 parts of water and 210 parts of trichloromethane were added dropwise 9.3 parts of ethyl 3-aminopyrrolidinecarboxylate. Upon completion, the reaction mixture was stirred for 15 minutes at room temperature. 10.7 Parts of calcium carbonate were added portionwise during a period of 10 minutes and stirring was continued overnight at room temperature. The reaction mixture was filtered and the separated organic layer was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The residue was distilled at 6.65 Pa, yielding 7.5 parts (69.3%) of ethyl 3-isothiocyanato-1-pyrrolidinecarboxylate; bp. 101° C. (interm 6).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-])=O)[C:5]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)=[C:4]([C:20](=[O:22])[CH3:21])[CH:3]=1.[H][H]>CO.[Pt]>[NH2:9][C:6]1[C:5]([C:12]2[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=2)=[C:4]([C:20](=[O:22])[CH3:21])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH3:8]
Reactant: [H][H]
Reactant: CC(=O)c1cc(Cl)c(C)c([N+](=O)[O-])c1-c1cc(F)cc(F)c1
Agent: [Pt]
Solvent: CO
Product: CC(=O)c1cc(Cl)c(C)c(N)c1-c1cc(F)cc(F)c1

Procedure:
A mixture of 1-(4-chloro-3′,5′-difluoro-5-methyl-6-nitrobiphenyl-2-yl)ethanone (8.61 g 26.4 mmol) in 160 mL of methanol was hydrogenated in the presence of 0.86 of 5% Pt/C, under ballon pressure of hydrogen, overnight. After filtering off catalyst, the filtrate was concentrated under reduced pressure to give the desired product. LCMS calculated for C15H13ClF2NO (M+H)+: m/z=296.1; Found: 296.1.
Reaction SMILES: [CH2:1]1[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH3:6].[CH2:8]([NH2:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17]>>[CH2:16]([NH:17][CH2:1][CH:2]([OH:7])[CH2:3][CH2:4][CH2:5][CH3:6])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][NH:18][CH2:1][CH:2]([OH:7])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC1CO1
Reactant: NCCCCCCCCCN
Product: CCCCC(O)CNCCCCCCCCCNCC(O)CCCC

Procedure:
Condensation of 1-hexene oxide and 1,9-nonanediamine affords N,N'-(1,9-nonylene)-bis[2-hydroxyhexylamine] (I: R = CH3 (CH2)3, R' = H, X = (CH2)9, Z = H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>ClCCl>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][CH:13]([CH2:16][OH:17])[CH2:14][O:15][S:31]([C:28]2[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=2)(=[O:33])=[O:32])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)[C@H]1CC[C@H](OC(CO)CO)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC[C@H](OC(CO)COS(=O)(=O)c2ccc(C)cc2)CC1
Reaction time: 16 h

Procedure:
To a solution of cis/trans-4-(2-hydroxy-1-hydroxymethyl-ethoxy)-cyclohexanecarboxylic acid ethyl ester (3:7) (0.74 g, 3.0 mmol) and triethylamine (0.42 ml, 3.0 mmol) in dichloromethane (30 ml) a catalytic amount of 4-N,N-dimethylaminopyridine was added. A solution of p-toluenesulfonyl chloride (0.57 g, 3.0 mmol) in dichloromethane (10 ml) was added dropwise at room temperature. Stirring for 16 h was followed by partitioning between ethyl acetate (100 ml) and 0.5 M aqueous hydrogen chloride solution (50 ml). The layers were separated. The aqueous layer was extracted with two portions of ethyl acetate. The combined organic layers were washed with one portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (0.46 g, 38%) as colorless oil. MS m/e: 401 (M+H+)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])(=O)=O.[I:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[N:24]=[CH:23][C:22]=1O.O.C(OCC)(=O)C>CN(C)C=O.C(#N)C>[I:20][C:21]1[C:22]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[CH:23][N:24]=[C:25]([O:27][CH3:28])[CH:26]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COc1cc(I)c(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(I)c(OCC(F)(F)F)cn1

Procedure:
466 mg (3.4 mmol, 2.0 eq.) of potassium carbonate and 567 mg (2.5 mmol, 1.5 eq.) of 2,2,2-trifluoroethyl trifluoromethanesulphonate were added to a solution of 455 mg (purity 93%, 1.7 mmol) of 4-iodo-6-methoxypyridin-3-ol in 10 ml of dimethylformamide and 0.4 ml of acetonitrile, and the mixture was irradiated in a microwave at 150° C. for 30 min. A further 393 mg (1.7 mmol, 1.0 eq.) of 2,2,2-trifluoroethyl trifluoromethanesulphonate were added, and the reaction mixture was once more irradiated in the microwave at 150° C. for 30 min. After addition of water/ethyl acetate and phase separation, the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried (sodium sulphate), filtered, concentrated under reduced pressure and dried. Yield: 500 mg (purity 94%, 94% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](O)=[O:24])=[CH:18][CH:17]=1.C(Cl)(=O)C(Cl)=O.[NH2:32][C:33]1[O:37][N:36]=[C:35]([CH:38]([CH3:40])[CH3:39])[CH:34]=1>C(Cl)Cl>[CH:38]([C:35]1[CH:34]=[C:33]([NH:32][C:23](=[O:24])[CH2:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:21][CH:20]=2)[O:37][N:36]=1)([CH3:40])[CH3:39]
Reactant: CC(C)c1cc(N)on1
Reactant: COc1cc2ncnc(Oc3ccc(CC(=O)O)cc3)c2cc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc(CC(=O)Nc4cc(C(C)C)no4)cc3)c2cc1OC
Temperature: 60 °C
Yield: 46.3 %

Procedure:
A mixture of 2-[4-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]acetic acid (0.3 g) and oxalyl chloride (3.73 ml) was heated at 60° C. for 30 minutes. The excess of oxalyl chloride was evaporated. Pyridine (0.43 ml) was added to a stirred mixture of the 2-[4-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]acetyl chloride so obtained, 5-amino-3-isopropylisoxazole (0.148 g) and methylene chloride (30 ml). The resultant mixture was stirred at ambient temperature for 30 minutes. The mixture was evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and ethyl acetate as eluent. There was thus obtained the title compound (0.183 g); 1H NMR: (DMSOd6) 1.89 (d, 6H), 2.92 (m, 1H), 3.75 (s, 2H), 3.97 (s, 3H), 4.0 (s, 3H), 6.18 (s, 1H), 7.26 (d, 2H), 7.39 (s, 1H), 7.41 (d, 2H), 7.55 (s, 1H), 8.53 (s, 1H), 11.83 (br s, 1H); Mass Spectrum: M+H+ 449.
Reaction SMILES: [CH:1]1([N:7]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:30][O:31][C:32](=[O:37])[C:33]([NH2:36])([CH3:35])[CH3:34]>>[CH:1]1([N:7]([CH2:25][CH:26]2[CH2:27][CH2:28]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][NH:36][C:33]([CH3:35])([C:32]([O:31][CH3:30])=[O:37])[CH3:34])=[CH:21][CH:22]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1
Reactant: COC(=O)C(C)(C)N
Agent: Cl
Product: COC(=O)C(C)(C)NCc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1

Procedure:
Following the general method as outlined in Example 73, starting from 6-[cyclohexyl(cyclopropylmethyl)amino]-N-(4-formylphenyl)pyrimidine-4-carboxamide (Intermediate 24) and 2-aminoisobutyric acid methyl ester hydrochloride (Sigma), the title compound was obtained as a colorless oil after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C@@H:12]1/[CH:17]=[CH:18]/[C:19]([C:21]1[O:22][C:23](Br)=[CH:24][CH:25]=1)=[O:20])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O.[BH4-].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)=O>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C@@H:12]1[CH2:17][CH2:18][CH:19]([OH:20])[C:21]1[O:22][C:23]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[CH3:34])=[CH:24][CH:25]=1)[CH3:2]
Reactant: CCOC(=O)CCCCCCN1C(=O)CC[C@@H]1/C=C/C(=O)c1ccc(Br)o1
Reactant: Cc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: CCOC(=O)CCCCCCN1C(=O)CC[C@@H]1CCC(O)c1ccc(-c2ccccc2C)o1
Temperature: 55 °C

Procedure:
7-{(R)-2-[(E)-3-(5-Bromo-furan-2-yl)-3-oxo-propenyl]-5-oxo-pyrrolidin-1-yl}-heptanoic acid ethyl ester was dissolved in anhydrous 1,4-dioxane (3 mL) under an argon atmosphere treated with potassium carbonate (130 mg, 0.94 mmol), 2-methylphenyl boronic acid (64 mg, 0.47 mmol), and bis(triphenylphosphine)palladiumdichloride (33 mg, 0.047 mmol). The yellow suspension was warmed to 55° C. for 15 hours and then the volatiles were removed. The mixture was then dissolved in methanol (10 mL) and stirred with sodium borohydride (ca. 35 mg, 0.9 mmol) for 20 minutes at ambient temperature and treated with acetone (1 mL). After removal of the volatiles, the residue was treated with methanol and the volatiles were removed once again. The residue was loaded onto 1 mm thick silica plates and the plates were developed two-times with 3% iso-propanol in dichloromethane. 7-{(S)-2-[3-hydroxy-3-(5-o-tolyl-furan-2-yl)-propyl]-5-oxo-pyrrolidin-1-yl}-heptanoic acid ethyl ester (54 mg) was obtained as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.Cl.[CH3:13][C:14]([CH3:24])([CH3:23])[C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:13][C:14]([CH3:24])([CH3:23])[C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=2)[CH2:19][CH2:18]1)=[O:16]
Reactant: CC(C)(C)C(=O)N1CCNCC1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(N2CCN(C(=O)C(C)(C)C)CC2)ncc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Stir a solution of 2-chloro-4-methyl-5-nitro-pyridine (0.85 mmol, 0.15 g), 2,2-dimethyl-1-piperazin-1-yl-propan-1-one hydrochloride (0.94 mmol, 0.16 g) and triethylamine (2.12 mmol, 0.3 mL) in a sealed tube at 80° C. overnight. Cool down the mixture to room temperature, add CH2Cl2 and wash with saturated aq. sodium chloride. Dry over sodium sulfate, filter, and concentrate under reduced pressure to give 2,2-dimethyl—[4-(4-methyl-5-nitro-pyridin-2-yl)-piperazin-1-yl]-propane-1-one. Subject residue to silica gel chromatography eluting with hexanes/ethyl acetate in a gradient (from 30% up to 60%). MS(ES): m/z=307 [M+H].
Reaction SMILES: [CH3:1][C:2](=[CH:5][CH:6]([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])[CH:3]=[O:4].CC(=CCBr)C=O>>[CH3:1][CH:2]([CH2:5][CH:6]([O:7][CH2:8][CH3:9])[O:10][CH2:11][CH3:12])[CH:3]=[O:4]
Reactant: CCOC(C=C(C)C=O)OCC
Agent: CC(C=O)=CCBr
Product: CCOC(CC(C)C=O)OCC
Yield: 89 %

Procedure:
The procedure described in Example 3 is repeated but 11.9 g of 2-methyl-4,4-diethoxy-2-butenal is used insteat of 16.3 g of 2-methyl- 4-bromo-2-butenal. Pure 2-methyl-4,4-diethoxybutanal is obtained in a yield of 89% of theory.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH2:4][O:5][C:6]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:7]=2[C:8]=1[C:9]([OH:11])=[O:10].[OH-].[Na+].Cl.[CH2:25](O)[CH3:26]>O1CCCC1>[F:21][C:2]([F:1])([F:20])[C:3]1[CH2:4][O:5][C:6]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:7]=2[C:8]=1[C:9]([O:11][CH2:25][CH3:26])=[O:10]
Reactant: CCO
Reactant: O=C(O)C1=C(C(F)(F)F)COc2ccc3ccccc3c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C(F)(F)F)COc2ccc3ccccc3c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
Preparation of 2-trifluoromethyl-3H-naphthopyran-carboxylic acid. A solution of the ester from Step 1 (0.8 g, 2.5 mmol) was dissolved in 40 mL of ethanol and 10 mL of tetrahydrofuran, treated with sodium hydroxide (2.5 N, 10 mL, 25 mmol) and stirred at room temperature for 16 hours. The reaction mixture was acidified with 1.0 N HCl, whereupon a solid formed that was isolated by filtration. The solid was washed with 20 mL of water to afford 0.7 g (95%) of the title compound as a yellow solid: mp 245.9-248.6° C. 1H NMR (acetone-d6 /300 MHz) 8.57 (s, 1H), 8.28 (d, 1H, J=8.7 Hz), 8.03 (d, 1H, J=9.0 Hz), 7.93 (d, 1H, J=8.7), 7.67 (m, 1H), 7.50 (m, 1H), 7.28 (d, 1H, J=9.0), 5.96 (qH-F, 1H, J=7.2 Hz). FABHRMS m/z 295.0561 (M+H, Calc'd 295.0582). Anal. Calc'd for C15H9O3F3 +3.31% H2O: C, 59.21; H, 3.35. Found: C, 59.17; H, 3.07.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:24]3[C:25]4=[C:26]5[C:21](=[CH:22][CH:23]=3)[CH:20]=[C:19](B3OC(C)(C)C(C)(C)O3)[CH:18]=[C:17]5[CH:16]=[CH:15][C:14]4=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:24]3[C:25]4=[C:26]5[C:21](=[CH:22][CH:23]=3)[CH:20]=[C:19]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:18]=[C:17]5[CH:16]=[CH:15][C:14]4=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Brc1ccccc1
Reactant: CC(C)(C)c1ccc(-c2ccc3ccc4cc(B5OC(C)(C)C(C)(C)O5)cc5ccc2c3c45)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(-c2ccc3ccc4cc(-c5ccccc5)cc5ccc2c3c45)cc1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
A mixed solution of 0.61 g of 2-[1-(4-t-butylphenyl)pyren-7-yl]-4,4,5,5-tetramethyl 1,3,2-dioxaborolane, 0.28 mL of bromobenzene, 1.2 g of tripotassium phosphate, 0.18 g of tetrabutylammonium bromide, 14 mg of palladium acetate and 15 mL of dimethylformamide was heated and stirred under a nitrogen gas stream at 130° C. for 8 hours. The solution was cooled to room temperature and poured into 75 mL of water, and then the precipitated solid was collected by filtration. The resulting solid was dissolved in dichloromethane, washed with water, dried over magnesium sulfate and then concentrated. The resulting crude product was purified by column chromatography and then vacuum-dried to obtain 0.49 g of 1-(4-t-butylphenyl)-7-phenylpyrene.