Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][CH:3]([C@@H:5]1[CH2:10][O:9][CH2:8][CH2:7][NH:6]1)[CH3:4].[Cl:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH2:19])[N:13]=1.CCN(C(C)C)C(C)C>C(#N)CC>[Cl:11][C:12]1[CH:17]=[C:16]([N:6]2[CH2:7][CH2:8][O:9][CH2:10][C@H:5]2[CH:3]([CH3:4])[CH3:2])[N:15]=[C:14]([NH2:19])[N:13]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CC(C)[C@@H]1COCCN1
Agent: Cl
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H]1COCCN1c1cc(Cl)nc(N)n1
Temperature: 110 °C
Yield: 80.5 %

Procedure:
(3R)-3-(1-Methylethyl)morpholine HCl salt (3.50 g, 21.1 mmol) and 4,6-dichloro-2-pyrimidinamine (3.81 g, 23.2 mmol, 1.1 equiv) were charged into a 60 mL sealable tube, followed with addition of 20 mL of propionitrile and Hunig's base (11.1 mL, 63.4 mmol, 3 equiv). The vessel was sealed and heated at 110° C. in an oil bath for 68 hours. The mixture was concentrated in vacuo, and the residue was partitioned between water (50 mL) and EtOAc (150 mL). The aqueous was extracted with another 100 mL of EtOAc. The combined organic was dried over Na2SO4, filtered, and concentrated in vacuo. The foamy residue was taken up in CHCl3 with some EtOAc to give a suspension, which was filtered. The solids collected were mostly starting 4,6-dichloro-2-pyrimidinamine. The filtrate underwent silica gel column chromatography using gradient elution of 1% EtOAc in CHCl3 to 80% EtOAc in CHCl3 to afford the title compound (4.36 g) as a glassy foam. LC-MS (ES) m/z=257 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:21][C@@H:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][C@H:23]3[NH2:31])=[N:6][C:7]([CH:18]3[CH2:20][CH2:19]3)=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])[N:9]=2)[CH2:3][CH2:2]1.[CH3:32][O:33][CH2:34][CH:35]=O.[BH3-]C#N.[Na+]>CO.C(O)(=O)C.C([O-])(O)=O.[Na+]>[CH:1]1([C:4]2[C:5]([NH:21][C@@H:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][C@H:23]3[NH:31][CH2:35][CH2:34][O:33][CH3:32])=[N:6][C:7]([CH:18]3[CH2:19][CH2:20]3)=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])[N:9]=2)[CH2:2][CH2:3]1
Reactant: COCC=O
Reactant: N[C@@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(Cl)cc2Cl)nc1C1CC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COCCN[C@@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(Cl)cc2Cl)nc1C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
To a solution of (1R,2R)-N1-[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]-2,3-dihydro-1H-indene-1,2-diamine (0.10 g, 0.22 mmol) in MeOH (2 mL) containing acetic acid (2 drops) and methoxyacetaldehye (49 mg, 0.66 mmol) was added NaBH3CN (1 M solution in THF, 0.8 mL, 0.8 mmol). The mixture was stirred at rt overnight. Dilute with sat. aq. NaHCO3 and extract ED with EtOAc (3×30 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated to afford an oil that was purified by biotage MPLC (90 g column, 10% ethyl acetate/hexanes) to afford 0.11 g (20%) of (1R,2R)-N1-[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]-N2-(2-methoxyethyl)-2,3-dihydro-1H-indene-1,2-diamine as a solid: 1H NMR (CDCl3) δ 0.60–1.01, 1.45–1.70, 2.83–2.99, 3.22–3.33, 3.47–3.56, 5.19, 5.53, 7.11–7.42; MS (ESI+) for C28H30Cl2N4O m/z 5.09 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O.[C@@H:18]1([NH2:28])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][NH:28][C@@H:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1cccc(Oc2cc(Cl)cc(Cl)c2)c1
Product: Clc1cc(Cl)cc(Oc2cccc(CN[C@H]3CCCc4ccccc43)c2)c1

Procedure:
3-(3,5-Dichlorophenoxy)benzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7][CH:8]=[CH:9][CH2:10][N:11]1[C:15](=[O:16])[N:14]([CH3:17])[C:13](=[O:18])[NH:12]1)=[O:4].[H][H]>C(COC)OC.[Pd]>[CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15](=[O:16])[N:14]([CH3:17])[C:13](=[O:18])[NH:12]1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)CCCC=CCn1[nH]c(=O)n(C)c1=O
Agent: [Pd]
Solvent: COCCOC
Product: COC(=O)CCCCCCn1[nH]c(=O)n(C)c1=O
Yield: 98.4 %

Procedure:
The 1-(6'-methoxycarbonyl-n-hex-2-enyl)-4-methyl-1,2,4-triazolidine-3,5-dione (12.4 g, 0.0486 mol) was dissolved in dimethoxyethane (200 ml) and 10% palladium on charcoal (3 g) was added and the resultant mixture was allowed to take up hydrogen (ca. 1100 mls). After the reaction was complete the resultant mixture was filtered through a kieselguhr bed and the filtrate evaporated in vacuo to afford 1-(6'-methoxycarbonyl-n-hexyl)-4-methyl-1,2,4-triazolidine-3,5-dione (12.3 g).
Reaction SMILES: O[NH:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1.[C:22]([O:26][C:27]([NH:29][C:30]1([C:33](O)=[O:34])[CH2:32][CH2:31]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[C:22]([O:26][C:27](=[O:28])[NH:29][C:30]1([C:33]([NH:2][C:3](=[O:21])[CH2:4][C:5]2[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:7][CH:6]=2)=[O:34])[CH2:31][CH2:32]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: O=C(Cc1ccc(CCCCc2ccccc2)cc1)NO
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC1(C(=O)NC(=O)Cc2ccc(CCCCc3ccccc3)cc2)CC1
Reaction time: 8 h

Procedure:
N-hydroxy-2-(4-(4-phenylbutyl)phenyl)acetamide 174 (1 equiv, 156 mg, 0.55 mmol) was dissolved in DMF (3 mL). 1-(tert-butoxycarbonylamino)cyclopropanecarboxylic acid (1.5 equiv, 166 mg, 0.83 mmol) was then added followed by the sequential addition of HOBt (1 equiv, 74 mg, 0.55 mmol) and EDC (1.5 equiv, 158 mg, 0.83 mmol). The reaction was then stirred overnight. The reaction was then partitioned between EtOAc (5 mL) and H2O (5 mL). The organic phase was separated, dried over Na2SO4, filtered and concentrated. The residue was purified by trituration with Et2O to afford tert-butyl-1-((2-(4-(4-phenylbutyl)phenyl)acetamidooxy)carbonyl)cyclopropylcarbamate in 166 mg (65%). LRMS: 466.5 (calc) 489.3 (MNa)+.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([C:21]([O:23][CH3:24])=[O:22])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:25][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>C1COCC1>[Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[C:11]([CH3:25])([C:21]([O:23][CH3:24])=[O:22])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C1(C)C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
To a solution of 1-tert-butyl 2-methyl (2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}pyrrolidine-1,2-dicarboxylate (5.11 g, 14.2 mmol) in dry THF (60 mL) at −78° C. was dropwise added lithium bistrimethylsilylamide (17.0 mL, 17.0 mmol, 1.0 M in THF). After being stirred for 30 minutes, iodomethane (1.77 mL, 28.4 mmol) was then added. The mixture was stirred at −78° C. for one hour, warmed to 0° C. for one hour and finally quenched with NaHCO3/H2O. The resulting mixture was extracted twice with ethyl acetate. The combined extracts were dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with hexane to 5% ethyl acetate/hexane to provide 2.66 g (50%) of a mixture of product isomers as a colorless oil. LC/MS (M-Boc+H)+ m/z=274.1. 1H NMR (CDCl3) δ 4.38 (m, 1H), 3.71 (m, 4H), 3.36 (m, 1H), 1.84-2.35 (m, 2H), 1.61 (m, 3H), 1.44 (m, 9H), 0.88 (m, 9H), 0.07 (m, 6H).
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[C:5]([C:13]([O-:15])=[O:14])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CO>[O:1]=[S:2]1(=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[C:5]([C:13]([OH:15])=[O:14])[CH2:4][CH2:3]1
Reactant: O=C([O-])C1=Cc2ccccc2S(=O)(=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1=Cc2ccccc2S(=O)(=O)CC1
Temperature: 60 °C
Reaction time: 24 h
Yield: 40.1 %

Procedure:
Into a solution of methyl 7-(2-propoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.67 g) in THF/methanol (10/5 ml) was added at room temperature an aqueous solution (2.1 ml) of potassium carbonate (622 mg), and the resulting mixture was stirred at 60° C. for 24 hours. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate. To the aqueous layer was added 1 N hydrochloric acid (15 ml), and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain 7-(2-propoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (270 mg) as light yellow crystals.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:3][CH2:4][OH:5].N1C=CC=CC=1.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>C(Cl)Cl>[S:29]([C:26]1[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=1)([O:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:6][CH2:7][CH2:8][CH:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:31])=[O:30]
Reactant: CC(C)CCCC(C)CCCC(C)CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC(C)CCCC(C)CCCC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.7 %

Procedure:
Under a nitrogen atmosphere, a solution of 22.8 g (100 mmol) of 3,7,11-trimethyldodecanol and 9.48 g (120 mmol) of pyridine in 200 ml of dry methylene chloride was added dropwise to a solution of 20.96 g (110 mmol) of p-toluenesulfonyl chloride in 100 ml of dry methylene chloride under ice cooling (1 to 2° C.). After the dropwise addition, the resultant was agitated at room temperature overnight, the resulting reaction solution was successively washed with 200 ml of water, 200 ml of 2N hydrochloric acid, and 200 ml of a saturated sodium bicarbonate water, and was dried over anhydrous magnesium sulfate. After the filtration, the resultant was concentrated to obtain 41.6 g of crude 3,7,11-trimethyldodecyl tosylate.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:28][NH2:29]>>[CH3:28][NH:29][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[C:15]=2[O:14]1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cccnc4)c3O2)cc1
Product: CNCC1Cc2cccc(-c3cccnc3)c2O1

Procedure:
The title compound was prepared (0.367 g, 70%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.730 g, 1.91 mmol) and methylamine (1.14 g, 36.7 mmol). mp 212-215° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:22]1C=CN=C1)=O.N>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9][C:10]([NH2:22])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Agent: N
Solvent: ClCCl
Product: NC(=O)CC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Reaction time: 2 h
Yield: 36 %

Procedure:
A solution of 3-(4-Bromo-phenyl)-3-(4-chloro-phenyl)-propionic acid* (0.25 g, 0.74 mmol) and 1,1′-carbonyldiimidazole (0.249, 1.47 mmol) in dichloromethane was stirred for 45 minutes before the addition of ammonia (2M solution in methanol, 3.68 ml, 7.36 mmol). The reaction mixture was stirred for 2 hours, solvent removed under reduced pressure and residue was purified over flash silica chromatography eluting with ethyl acetate/petroleum ether (1:4) to afford the title compound (0.091 g, 36% yield). LC/MS: (PS-A2) Rt 3.08 [M+H]+ 339.93.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=O)=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[NH:16][N:15]=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:10][C:6]1[N:5]=[CH:4][N:3]=[C:2]2[C:7]=1[CH:8]=[N:11][C:12]1[N:16]2[N:15]=[CH:14][CH:13]=1
Reactant: Nc1ccn[nH]1
Reactant: O=Cc1c(Cl)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Clc1ncnc2c1cnc1ccnn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.1 %

Procedure:
The product from Example 1a (1.24 g, 7.01 mmol) in 30 mL of THF was reacted with 5-aminopyrazole (0.58 g, 7.01 mmol) in 10 mL of THF under an argon atmosphere by dropwise addition. The mixture was stirred at room temperature for 1 hour and then added diisopropylethylamine (1.22 mL, 7.01 mmol) dropwise with stirring. The mixture was heated overnight at 60° C., and quenched with water and extracted with EtOAc, washed with brine, and dried over Na2SO4. The product was filtered and the solvent was removed under vacuum. The product was purified by silica gel chromatography eluting with EtOAc/hexane to give the title compound as a pale yellow solid (405 mg, 29%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:18][CH2:19][CH2:20][Cl:21]>>[Cl:21][CH2:20][CH2:19][CH2:18][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)=[CH:3][C:2]=1[F:1]
Reactant: N#Cc1ccc(-c2ccc(O)c(F)c2)cc1
Reactant: ClCCCBr
Product: N#Cc1ccc(-c2ccc(OCCCCl)c(F)c2)cc1
Yield: 99 %

Procedure:
The product from Example 167A and 1-bromo-3-chloropropane were processed as described in Example 164C to provide the title compound (99% yield). 1HNMR (300 MHz, CDCl3) δ2.30 (m, 2H), 3.80 (m, 2H), 4.25 (m, 2H), 7.12-7.75 (m, 7H); MS (DCI) m/z 290 (M+H)+.
Reaction SMILES: [N:1]([O-])=O.[Na+].[C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([NH2:17])=[CH:9][CH:8]=1)#[N:6]>O.Cl>[C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([NH:17][NH2:1])=[CH:9][CH:8]=1)#[N:6]
Reactant: O=N[O-]
Reactant: N#Cc1ccc(N)c2ccccc12
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(NN)c2ccccc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 4.09 g of sodium nitrite in 30 ml of water is added to a solution, cooled to 0° C., of 8.35 g of 4-cyano-1-naphthylamine in 180 ml of 1N HCl. The mixture is left stirring for 1 hour 15 minutes at 0° C. It is cooled to -10° C., and a solution of 41.75 g of stannous chloride dihydrate in 42 ml of concentrated HCl is added slowly. The reaction mixture is stirred for 1 hour, allowing the temperature to rise to RT. It is filtered. The residue is suspended in water and 20 ml of concentrated NaOH are added. The expected product is obtained after filtration, rinses with water and then drying under vacuum, m=8.6 g.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11](=[O:30])[C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].CC(C)=[O:33].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11](=[O:30])[C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:3]=1[C:4]([OH:33])=[O:5]
Reactant: CCCCCCc1ccc(-c2ccc(C(=O)Oc3ccc(C=O)c(Cl)c3)cc2)cc1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CCCCCCc1ccc(-c2ccc(C(=O)Oc3ccc(C(=O)O)c(Cl)c3)cc2)cc1
Reaction time: 3 h

Procedure:
The crude 2-chloro-4-{[p-(p-hexylphenyl)benzoyl]oxy}benzaldehyde (67.1 g) obtained was dissolved in 2500 ml of acetone. 80 ml of Jones' reagent were added dropwise to this solution within 45 minutes, the mixture warming slightly. The mixture was stirred for a further 3 hours, then the precipitated inorganic material was filtered off under suction and the acetone was distilled off on a rotary evaporator. The residue was suspended in water and the suspension was suction filtered. The crude 2-chloro-4-{[p-(p-hexylphenyl)benzoyl]oxy}benzoic acid obtained was washed neutral on the suction filter with water and then, for purification, boiled up with methanol, cooled, filtered off and dried. Yield 58.5 g; m.p. 163.8°-165.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][O:22][Si](C(C)(C)C)(C)C)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl>CO.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][OH:22])=[O:11])=[CH:30][CH:31]=1)([O-:3])=[O:2]
Reactant: CC(=O)S[C@H]1C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)S[C@H]1C[C@@H](CO)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
(2S,4S)-1-(p-Nitrobenzyloxycarbonyl)-2-t-butyldimethylsilyloxymethyl-4-acetylthiopyrrolidine (0.85 g) was dissolved in methanol (8.5 ml), and 0.85 ml of 6N hydrochloric acid was added thereto. The resulting mixture was stirred at room temperature for 2.5 hours, diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate and distilled to remove the solvent. Recrystallization of the residue from diethyl ether gave (2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-hydroxymethyl-4-acetylthiopyrrolidine.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[C:3]1[CH2:13][OH:14].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+]>ClCCCl>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[C:3]1[CH:13]=[O:14]
Reactant: Cn1cc(-c2ccccc2)nc1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1cc(-c2ccccc2)nc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
To a solution of (1-Methyl-4-phenyl-1H-imidazol-2-yl)-methanol 5 (50.0 mg, 0.266 mmol) in 1,2-dichloroethane (4.0 mL) under Ar was added Dess-Martin periodinane (124 mg, 0.292 mmol), and the mixture was stirred at room temperature for 2 hours. Saturated NaHCO3 solution was added, the organic layer was separated and the aqueous layer was extracted with 1,2-dichloroethane. The combined organic layers were dried over Na2SO4, volatiles were evaporated and the residue was purified by silica gel chromatography on a FlashMaster system (gradient elution; 0-100% ethylacetate in heptane) to afford the title compound as a white solid (39.1 mg, 79%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:33]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])(=[O:36])[CH:34]=[CH2:35]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:38]([O:37][C:33](=[O:36])[CH2:34][CH2:35][N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:31])([F:30])[F:32])[CH:23]=3)=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCc3ccc(Cl)c(C(F)(F)F)c3)cc2)CC1
Reactant: C=CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)CCN1CCC(c2ccc(OCc3ccc(Cl)c(C(F)(F)F)c3)cc2)CC1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
4-[4-(4-Chloro-3-trifluoromethyl-benzyloxy)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (1 eq) is dissolved in 10% TFA/DCM and stirred for 30 minutes. After concentration, the residue is re-dissolved in DCM and washed with saturated NaHCO3 and brine. The organic layer is dried over Na2SO4 and concentrated. The residue is then dissolved in MeOH and t-butyl acrylate (2 eq) is added. The resulting solution is heated at 90° C. in microwave for 10 minutes. After concentration, purification by flash column chromatography (80% EtOAc/hexane) gave 3-{4-[4-(4-Chloro-3-trifluoromethyl-benzyloxy)-phenyl]-piperidin-1-yl}-propionic acid tert-butyl ester. [MS: (ES+) 498.2 (M+1)+].
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([O:10][CH3:11])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].[C:12]([N:20]=[C:21]=[O:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:7]([C:6]1[C:5]([CH3:9])=[C:4]([O:10][CH3:11])[S:3][C:2]=1[NH:1][C:21]([NH:20][C:12](=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:22])#[N:8]
Reactant: COc1sc(N)c(C#N)c1C
Reactant: O=C=NC(=O)c1ccccc1
Product: COc1sc(NC(=O)NC(=O)c2ccccc2)c(C#N)c1C

Procedure:
Prepared as in Example 1a from 2-amino-5-methoxy-4-methylthiophene-3-carbonitrile (example 13b) and benzoyl isocyanate as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 2.03 (s, 3H), 3.86 (s, 3H), 7.54 (t, J=7.2 Hz, 2H), 7.67 (t, J=7.6 Hz, 1H), 8.01-8.03 (d, J=8.4 Hz, 2H), 11.60 (s, 1H), 12.03 (s, 1H). MS 316 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.N1CCOCC1.[CH3:16][C:17]1([CH3:27])[O:21][C:20](=[CH:22][C:23](Cl)=[O:24])[C:19](=[O:26])[O:18]1>C(Cl)Cl>[CH3:16][C:17]1([CH3:27])[O:21][C:20](=[CH:22][C:23]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)=[O:24])[C:19](=[O:26])[O:18]1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: NCc1ccc(F)cc1
Solvent: ClCCl
Solvent: C1COCCN1
Product: CC1(C)OC(=O)C(=CC(=O)NCc2ccc(F)cc2)O1
Reaction time: 1 h
Yield: 100.7 %

Procedure:
To a stirred suspension of 4-fluorobenzylamine (37.5 mg, 0.3 mmol) and resin bound morpholine (200 mg, 2.5–4.0 mmol/1 g) was added a solution of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (60 mg, 0.31 mmol) in CH2Cl2 (3 mL) and the mixture shaken for 1 h. The mixture was filtered and the filtrate concentrated to give the title product as a white solid (84.4 mg, 100% yield). MS calc for C14H14FNO4 (M+Na): 302.29; found: 302.29.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][CH2:12][OH:13].[Br:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][CH2:19][N:20]2[C:25](=[O:28])[CH2:26]Cl>C1COCC1.C(=O)(O)[O-].[Na+]>[Br:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][CH2:19][N:20]2[C:25](=[O:28])[CH2:26][O:13][CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([CH3:10])[C:4]=1[CH3:3]
Reactant: Cc1cccc(CCO)c1C
Reactant: O=C(CCl)N1CCCc2c(Br)cccc21
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(CCOCC(=O)N2CCCc3c(Br)cccc32)c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 11.2 %

Procedure:
To a suspension of sodium hydride (35.1 mg, 1.46 mmol) in anhydrous THF (3.0 mL) under nitrogen was added 2-(2,3-dimethylphenyl)ethanol (220 mg, 1.46 mmol). The reaction mixture was stirred at room temperature for 15 min and then a solution of 1-(5-bromo-3,4-dihydroquinolin-1(2H)-yl)-2-chloroethanone (352 mg, 1.22 mmol) in anhydrous THF (3.0 mL) was added. The resulting mixture was stirred at room temperature for 18 h. After this time, the reaction mixture was diluted with saturated sodium bicarbonate (55 mL) and then extracted with ethyl acetate (60 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was purified by preparative HPLC (PHENOMENEX® Axia Luna, 5μ, C18, 30×250 mm; 25 min gradient from 80% A:20% B to 0% A:100% B and 5 min 100% B (A=90% H2O/10% MeOH+0.1% TFA); (B=90% MeOH/10% H2O+0.1% TFA); detection at 220 nm) to afford the title compound (55 mg, 11% yield) as white powder. LCMS, [M+H]+=402.1. 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J=8.0 Hz, 1H), 7.30 (br. s, 1H), 7.02-6.96 (m, 4H), 4.20 (s, 2H), 3.74-3.69 (m, 2H), 3.66 (t, J=7.4 Hz, 2H), 2.92 (t, J=7.4 Hz, 2H), 2.78 (t, J=6.9 Hz, 2H), 2.24 (s, 3H), 2.18 (s, 3H), 1.99-1.90 (m, 2H).