Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:10](=[O:11])[C:9]2[NH:8][CH:7]=[N:6][C:5]=2[N:4]=[C:2]1[NH2:3].C[Si](C)(C)N[Si](C)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[O:33]1[CH2:37][CH2:36][O:35][CH2:34]1>>[OH:35][CH2:36][CH2:37][O:33][CH2:34][N:6]1[CH:7]=[N:8][C:9]2[C:10](=[O:11])[NH:1][C:2]([NH2:3])=[N:4][C:5]1=2
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Reactant: C1COCO1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Product: Nc1nc2c(ncn2COCCO)c(=O)[nH]1
Temperature: 70 °C
Yield: 78 %

Procedure:
A mixture of guanine (25 g) , hexamethyldisilazane (HMDS, 125 ml), and trimethylsilyl trifluoromethanesulfonate (1 ml) was heated to reflux (130°-135° C.) for 24 hours. The resulting mixture was cooled to 70° C., 1,3-dioxolane (25 ml) added, and the resulting mixture refluxed for 16 hours. Excess HMDS and 1,3-dioxolane were removed by distillation under reduced pressure. The reaction mixture was cooled to 70° C., and poured into a mixture of 600 ml of 10% aqueous acetic acid. The mixture was heated to give a solution. The hot solution was treated with a small amount of activated carbon (1.25 g) to remove any color, filtered, and the filtrate slowly cooled to 5° C. The white crystalline solid thus produced was filtered off, to yield pure 9-(2-hydroxyethoxymethyl)guanine (29 g, 78%). 1H NMR: 3.38 (4H, singlet); 4.64 (1H, broad singlet); 5.26 (2H, singlet); 6.54 (2H, broad singlet); 7.68 (1H, singlet).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH3:19][O:20][C:21](=[O:27])[C@@H:22]1[CH2:26][CH2:25][CH2:24][NH:23]1>CO.C(Cl)Cl>[CH3:19][O:20][C:21](=[O:27])[C@@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:15](=[O:17])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-proline methyl ester hydrochloride (Bachem), the title compound was prepared as a viscous solid. The reaction was monitored by tlc (Rf=0.57 in 10% MeOH/DCM) and the product was purified by acid/base washes.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][S:5][S:6][CH2:7][CH2:8][NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17].[CH2:19]1[C@@H:23]([CH2:24][CH2:25][CH2:26][CH2:27][C:28](O)=[O:29])[S:22][S:21][CH2:20]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[S:21]1[CH2:20][CH2:19][C@H:23]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]([NH:2][CH2:3][CH2:4][S:5][S:6][CH2:7][CH2:8][NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])=[O:29])[S:22]1
Reactant: NCCSSCCNC(=O)c1ccccc1O
Reactant: O=C(O)CCCC[C@@H]1CCSS1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(CCCC[C@H]1CCSS1)NCCSSCCNC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 23.6 %

Procedure:
The HCl salt of N-(2-(2-(2-aminoethyl)-disulfanyl)-ethyl)-2-hydroxybenzamide (0.322 mmol) was taken up in DMF (5 mL) along with (R)-α-lipoic acid (TCI, 66 mg, 0.322 mmol) HATU (134 mg, 0.354 mmol) and DIEA (170 μL, 0.97 mmol). The resulting reaction mixture was stirred at room temperature for 4 h. It was then diluted with EtOAc (30 mL) and washed successively with water (3×5 mL) and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. Purification by chromatography (CH2Cl2) afforded (S)—N-(2-(2-(2-(5-(1,2-dithiolan-3-yl)pentanamido)ethyl)disulfanyl)ethyl)-2-hydroxybenzamide (35 mg, 24%). Mass calculated for C19H28N2O3S4: 460.1. found: [M+H]+=461.
Reaction SMILES: C([Li])CCC.[Br:6][C:7](Br)=[CH:8][N:9]([CH:16]=[C:17](Br)[Br:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C(O)(=O)C.Cl>C1COCC1.[Cl-].[Zn+2].[Cl-]>[Br:6]/[CH:7]=[CH:8]\[N:9](/[CH:16]=[CH:17]\[Br:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: BrC(Br)=CN(C=C(Br)Br)c1ccccn1
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Br/C=C\N(/C=C\Br)c1ccccn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
An oven-dried 500 mL, 3-neck flask with magnetic stirrer, addition funnel, thermocouple and nitrogen inlet was charged with anhydrous zinc chloride (15.0 g, 0.11 mol) and cooled in an ice/salt bath. 100 mL of THF was then added dropwise. Butyllithium (134 mL, 2.5 M in hexanes, 0.34 mol) was then added dropwise such that the temperature was maintained below 0° C., giving a milky white solution that was stirred at 0° C. for 30 minutes. The ice/salt bath was replaced with a dry ice/acetone bath and the reaction cooled to −75° C. N,N-bis(2,2-dibromovinyl)pyridin-2-amine (5.0 g, 0.011 mol) in 50 mL of THF was added dropwise and the reaction stirred at −75° C. for 20 h. While still at −75° C., 100 mL of 10% acetic acid in THF was added dropwise and the cold solution poured into 150 mL of 1 N HCl. The reaction mixture was extracted with 3×100 mL of ether and the combined organics were washed with 2×100 mL of saturated NaHCO3, dried and evaporated leaving 3.0 g of an colorless liquid as the product.
Reaction SMILES: C=O.[CH2:3]([NH2:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]CCCCCCCCCC.CC1C(O)=C(C)C(C)=C(C=1)[OH:28]>C(O)(C)C>[O:28]1[C:10]2=[CH:9][CH:8]=[CH:7][CH2:6][CH:5]2[CH2:4][CH2:3][NH:21]1
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: CCCCCCCCCCCCCCCCCCN
Agent: C=O
Solvent: CC(C)O
Product: C1=CCC2CCNOC2=C1
Temperature: 25 °C
Yield: 272.1 %

Procedure:
A 500 ml four-neck flask was initially charged with 30 g of paraformaldehyde at room temperature in 100 ml of isopropanol. 142 g of molten n-octadecylamine were added rapidly. The flask contents were heated to reflux and stirred under reflux for 30 minutes. 76 g of trimethylhydroquinone were added in 3 portions within 15 minutes. The mixture was stirred under reflux for 30 minutes. In the course of cooling to room temperature, a solid precipitated out and was filtered off with suction through a D3 suction filter. The filter residue was washed repeatedly with heptane. Subsequently, the residue was dried overnight in a vacuum drying cabinet at 50° C. and 100 mbar under nitrogen atmosphere. 186.4 g of product were obtained.
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[C:11]([S:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:12]3[C:13](Br)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].[CH3:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.C([O-])(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)CC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([S:20][C:11]2[C:12]3[C:13]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[CH3:28])=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]3[CH2:8][CH2:7][CH:6]([CH2:2][C:3]([OH:5])=[O:4])[C:10]=23)=[CH:22][CH:23]=1
Reactant: CC(C(=O)[O-])C1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Reactant: Cc1ccccc1B(O)O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Product: Cc1ccccc1-c1cc(F)cc2c1c(Sc1ccc(Cl)cc1)c1n2CCC1CC(=O)O
Temperature: 80 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
To (+/−)-methyl[8-bromo-9-[(4-chlorophenyl)sulfanyl]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate (Example 7, Step 9, 100 mg, 0.21 mmol) in 1-propanol (2 mL) were added 2-methylphenylboronic acid (57 mg, 0.42 mmol), 3:1 mixture of triphenylphosphine/palladium (>) acetate (11 mg) and 2M aqueous potassium carbonate (0.3 mL). The mixture was degassed and stirred at 80° C. for 6 h and the reaction mixture was cooled to r.t. Then THF (3 mL) and 1N LiOH were added and the mixture was stirred for 2 h at r.t. AcOH (0.5 mL) and brine were added and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 40% EtOAc/hexane containing 1% AcOH to give 90 mg of the title compound.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10](C(CC)=O)[CH3:11]>>[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:9])[CH2:10][CH3:11]
Reactant: O=C(O)c1ccccc1
Reactant: CCC(=O)CC
Product: CCC(=O)c1ccccc1

Procedure:
A method according to claim 1 wherein the ketone is diethyl ketone and the carboxylic acid is benzoic acid to yield propiophenone.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]([O:17]CC)=[O:16])[C:11]=3[CH:20]=2)=[N:4][N:3]=1>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]([OH:17])=[O:16])[C:11]=3[CH:20]=2)=[N:4][N:3]=1
Reactant: CCOC(=O)c1coc2ccc(-c3nnc(C)o3)cc12
Solvent: CCO
Product: Cc1nnc(-c2ccc3occ(C(=O)O)c3c2)o1
Yield: 32 %

Procedure:
In the same manner as in Example 134 and using ethyl 5-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-3-carboxylate instead of methyl 4-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-3-yl]benzoate and ethanol instead of methanol, the title compound (yield 32%) was obtained as pale-yellow crystals.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH3:15][C:16]([CH3:18])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([NH:1][CH:16]([CH3:18])[CH3:15])[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 95.7 %

Procedure:
To a 50 L 3-neck round-bottom reaction flask equipped with a mechanical stirrer, temperature probe, nitrogen inlet and cooling bath was added 4-amino-1-benzylpiperidine (2,000 g, 10.5 mol) and dichloromethane (20 L). Acetone (610.5 g, 10.5 mol) was added and the reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was then cooled to 0° C. to 5° C. with an ice/methanol bath and sodium triacetoxyborohydride (2,673 g, 12.6 mol) was added while maintaining the temperature of the reaction mixture below 25° C. The cooling bath was then removed and the reaction mixture was stirred until less than 1% starting material was present by gas chromatograhy (GC) analysis (about 3 hours). Concentrated hydrochloric acid was added until the pH of the reaction mixture was 7 (about 500 mL). The resulting slurry was filtered through a polypropylene filter pad and the solids were washed with dichloromethane (2×2 L). The solids were saved for use after concentration of the filtrate. The filtrate was concentrated at 40° C. until no condensate remained. In a 40 L separatory funnel, the solids and distillation residue were dissolved in water (15 L) and concentrated hydrochloric acid was added until the pH of the solution was 3 (about 2.5 L). The aqueous layer was then washed with dichloromethane (2×2 L). The pH of the aqueous layer was adjusted to 11 to 12 with 50% aqueous sodium hydroxide solution (about 4.5 L) and this mixture was extracted with dichloromethane (5×3 L). The organic layers were combined, decolorized with charcoal (50 g) and dried over anhydrous magnesium sulfate (200 g). The solids were filtered off using a glass fiber filter pad and the filtrate was concentrated until no condensate remained to afford the title compound (2,336 g, 96% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:30](=[CH:31][CH:32]=1)[O:29][C:7]1([CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]4[C:17](=[C:18]([O:27][CH3:28])[CH:19]=[CH:20][CH:21]=4)[N:16]=3)=[O:14])[CH2:9][CH2:8]1)[CH2:6][C:5]2=[O:33].[NH2:34][C:35]1[N:39]([CH3:40])[N:38]=[CH:37][CH:36]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:26][O:25][C:23]1[C:22]2[C:17](=[C:18]([O:27][CH3:28])[CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:13]([N:10]2[CH2:11][CH2:12][C:7]3([CH2:6][C:5](=[O:33])[C:4]4[C:30](=[CH:31][CH:32]=[C:2]([NH:34][C:35]5[N:39]([CH3:40])[N:38]=[CH:37][CH:36]=5)[CH:3]=4)[O:29]3)[CH2:8][CH2:9]2)=[O:14])[CH:24]=1
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(Br)ccc2O3)nc2c(OC)cccc12
Reactant: Cn1nccc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1COCCO1
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(Nc4ccnn4C)ccc2O3)nc2c(OC)cccc12
Temperature: 120 °C

Procedure:
The bromide compound (2.00 g) produced in Example 9, 5-amino-1-methyl-1H-pyrazole (456 mg), palladium acetate (175 mg), 2-(di-t-butylphosphino)biphenyl (233 mg) and cesium carbonate (1.66 g) were suspended in 1,4-dioxane (20 mL), and heated under reflux at 120° C. for 40 hours. The reaction liquid was filtered through Celite, the residue on the Celite was washed with chloroform, and the filtrate was concentrated under reduced pressure. The resulting residue was purified through silica gel column chromatography (developed with solvents of ethyl acetate/acetone=6/4 and chloroform/methanol=99/1 in order) to obtain the intended compound as a yellow amorphous solid. 1H-NMR (400 MHz, CDCl3) δ: 7.77 (1H, dd, J=8.3, 1.0 Hz), 7.49-7.43 (2H, m), 7.22 (1H, d, J=2.8 Hz), 7.17 (1H, s), 7.08 (1H, dd, J=7.8, 1.0 Hz), 6.97 (1H, dd, J=8.8, 2.8 Hz), 6.91 (1H, d, J=8.8 Hz), 5.97 (1H, d, J=2.0 Hz), 5.42 (1H, s), 4.60-4.52 (1H, m), 4.18-4.10 (1H, m), 4.07 (3H, s), 4.03 (3H, s), 3.68 (3H, s), 3.65-3.55 (1H, m), 3.40-3.29 (1H, m), 2.77 (1H, d, J=16.6 Hz), 2.71 (1H, d, J=16.6 Hz), 2.25-2.15 (1H, m), 2.10-2.02 (1H, m), 1.92-1.79 (2H, m). MS [M+H]+=528.
Reaction SMILES: C1(COC2N=C(C(O)=O)C=CC=2C)CC1.[CH:16]1([CH2:19][C@H:20]([NH:26][C:27]([C:29]2[CH:34]=[CH:33][C:32]([CH:35]3CCOCC3)=[C:31]([O:41][CH2:42][CH:43]3[CH2:45][CH2:44]3)[N:30]=2)=[O:28])[C:21]2[S:22][CH:23]=[CH:24][N:25]=2)[CH2:18][CH2:17]1>>[CH:16]1([CH2:19][C@H:20]([NH:26][C:27]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([O:41][CH2:42][CH:43]3[CH2:45][CH2:44]3)[N:30]=2)=[O:28])[C:21]2[S:22][CH:23]=[CH:24][N:25]=2)[CH2:17][CH2:18]1
Reactant: O=C(N[C@@H](CC1CC1)c1nccs1)c1ccc(C2CCOCC2)c(OCC2CC2)n1
Agent: Cc1ccc(C(=O)O)nc1OCC1CC1
Product: Cc1ccc(C(=O)N[C@@H](CC2CC2)c2nccs2)nc1OCC1CC1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid (Example 36 d) and (S)-2-cyclopropyl-1-thiazol-2-yl-ethylamine (Example 59 b) as starting materials, MS (LC/MS): 358.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([O:12][CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)[C:5](Br)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]2[O:12][CH2:13][C@H:14]3[CH2:18][CH2:17][CH2:16][N:15]3[C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(N)ccc(Br)c1OC[C@H]1CCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1c(N)ccc2c1OC[C@H]1CCCN21
Temperature: 100 °C
Yield: 42.4 %

Procedure:
A mixture of methyl 6-amino-3-bromo-2-((R)-1-pyrrolidin-2-ylmethoxy)benzoate (Intermediate 7, 1.65 g), palladium acetate (0.281 g), (+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (1.56 g) and cesium carbonate (3.26 g) in toluene (40 mL) was heated at 100° C., under an atmosphere of nitrogen for 2 hours. The mixture was cooled and partitioned between ethyl acetate and water. The organic layer was dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-40% to give methyl (R)-7-amino-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-6-carboxylate (0.528 g) as a dark oil.
Reaction SMILES: [CH3:1][C:2]([CH3:44])([CH3:43])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([C:34]([CH:36]2[CH2:41][CH2:40][CH:39]([CH3:42])[CH2:38][CH2:37]2)=[O:35])[CH:14]2[CH2:19][CH2:18][CH:17]([O:20][C:21]3[N:26]=[C:25]([O:27]CC[Si](C)(C)C)[CH:24]=[CH:23][N:22]=3)[CH2:16][CH2:15]2)[CH:6]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:1][C:2]([CH3:43])([CH3:44])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([C:34]([CH:36]2[CH2:37][CH2:38][CH:39]([CH3:42])[CH2:40][CH2:41]2)=[O:35])[CH:14]2[CH2:15][CH2:16][CH:17]([O:20][C:21]3[NH:26][C:25](=[O:27])[CH:24]=[CH:23][N:22]=3)[CH2:18][CH2:19]2)[CH:6]=1
Reactant: CC1CCC(C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)C2CCC(Oc3nccc(OCC[Si](C)(C)C)n3)CC2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1CCC(C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)C2CCC(Oc3nccc(=O)[nH]3)CC2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.5 %

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-((4-methyl-cyclohexanecarbonyl)-{4-[4-(2-trimethylsilanyl-ethoxy)-pyrimidin-2-yloxy]-cyclohexyl}-amino)-thiophene-2-carboxylic acid (37 mg, 0.058 mmol) in THF (1 mL) was treated with tetrabutylammonium fluoride (0.087 mL, 1M in THF, 0.087 mmol) and stirred at ambient temperature for 1.5 h. An additional portion of tetrabutylammonium fluoride (0.290 mL) was added and the reaction mixture was stirred at ambient temperature for 3 h. After concentration the residue was purified by HPLC with CH3CN (0.1% TFA)/H2O (0.1% TFA) to afford 18 mg (58% yield) of Compound 326: MS (m/z): 537.9 [M+H]−; HPLC retention time 4.28 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([NH:19][CH3:20])[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:21](OCC)=[O:22].[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:32][C:21]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][C:9]([CH2:12][N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[CH:8][C:7]=3[NH:19][CH3:20])=[O:22])=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1cnc2c(NC)cc(CN3CCOCC3)cc2c1O
Reactant: NCc1ccc(Cl)cc1
Product: CNc1cc(CN2CCOCC2)cc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc12
Temperature: 200 °C

Procedure:
A mixture of ethyl 4-hydroxy-8-(methylamino)-6-(4-morpholinylmethyl)-3-quinolinecarboxylate (280 mg) and 4-chlorobenzylamine (1.5 mL) is heated under nitrogen at 200° C. for 30 min. The bulk of the 4-chlorobenzylamine is removed under reduced pressure, and the product is purified by chromatography on silica gel to give 169 mg of the title compound as an oil.
Reaction SMILES: [Br-].[Br:2][CH2:3][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].C([O:35][C@H:36]([C@@H:38]1[C@:46]2([CH3:47])[C@H:41]([C:42](=O)[CH2:43][CH2:44][CH2:45]2)[CH2:40][CH2:39]1)[CH3:37])=O.S(=O)(=O)(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O1CCOCC1.CCOCC.O>[Br:2]/[CH:3]=[C:42]1\[CH2:43][CH2:44][CH2:45][C@@:46]2([CH3:47])[C@H:41]\1[CH2:40][CH2:39][C@@H:38]2[C@@H:36]([OH:35])[CH3:37]
Reactant: BrC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[C@H](OC=O)[C@H]1CC[C@H]2C(=O)CCC[C@]12C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Solvent: CCOCC
Product: C[C@H](O)[C@H]1CC[C@H]2/C(=C/Br)CCC[C@]12C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 46.5 %

Procedure:
Under a nitrogen atmosphere, a suspension of bromomethyltriphenylphosphonium bromide (319 mg, 0.7304 mmol) in toluene (0.4 ml) was cooled in an ice bath, and potassium hexamethyldisilazide (0.5 M in toluene, 1.3 ml, 0.6492 mmol) was added dropwise thereto. The reaction mixture was stirred at 0° C. for 1 hour and 20 minutes, and at room temperature for 8 minutes, and then heated to 42° C. A solution of (S)-1-{(3S,3aR,7aR)-octahydro-3a-methyl-7-oxo-1H-indene-3-yl}ethyl formate (Compound 17: 36.4 mg, 0.1623 mmol) in toluene (0.25 ml) was added thereto. The vessel of (S)-1-{(3S,3aR,7aR)-octahydro-3a-methyl-7-oxo-1H-indene-3-yl}ethyl formate (Compound 17) was washed with toluene (0.1 ml×2) and the washings were added. The reaction mixture was stirred at from 41° C. to 46° C., and then cooled in an ice bath. Saturated aqueous ammonium chloride solution (2 ml), water (5 ml) and methanol (1.5 ml) were added thereto, and the resulting mixture was extracted with hexane (25 ml). The organic layer was washed with saturated brine (5 ml), dried over sodium sulfate, and evaporated under reduced pressure. The obtained crude product (169.4 mg) was dissolved in dioxane (0.5 ml), and the resulting mixture was cooled in an ice bath. To the mixture, 50 v/v % sulfuric acid (0.5 ml) was added, and the reaction mixture was stirred at room temperature (22° C.) for 1.5 hours. After cooling the resulting mixture in an ice bath, the mixture was diluted with ether (10 ml). Potassium carbonate (0.56 g) and water (5 ml) were added thereto. After separating the organic layer, the aqueous layer was extracted twice with ether (10 ml). The combined organic layer was washed with saturated brine (5 ml), dried over sodium sulfate, and evaporated under reduced pressure. The obtained crude product was purified by flash column chromatography to obtain (S)-1-{(E,3S,3aS,7aR)-7-(bromomethylene)-octahydro-3a-methyl-1H-indene-3-yl}ethanol (20.6 mg, 46.5%).
Reaction SMILES: Cl.C([O:5][C:6]1[C:7]([CH3:23])=[N:8][C:9]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:10]([CH2:14]Cl)[C:11]=1[CH2:12]Cl)(=O)C.[CH3:24][NH2:25]>CS(C)=O>[CH3:24][N:25]1[CH2:12][C:11]2[C:6]([OH:5])=[C:7]([CH3:23])[N:8]=[C:9]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]=2[CH2:14]1
Reactant: CC(=O)Oc1c(C)nc(Cc2ccccc2)c(CCl)c1CCl
Reactant: CN
Agent: Cl
Solvent: CS(C)=O
Product: Cc1nc(Cc2ccccc2)c2c(c1O)CN(C)C2
Temperature: 80 °C

Procedure:
A mixture of 37.5 g (100 millimoles) of 2-methyl-4,5-di-(chloromethyl)-6-benzyl-pyridin-3-yl acetate hydrochloride (Example 4), 50 ml of dry dimethylsulfoxide and 16 g (500 millimoles) of methylamine is heated for 5 hours at 80° C. in an autoclave. The solvent is stripped off in a high vacuum and the residue is partitioned between methylene chloride and water, taking care that the pH of the aqueous phase is 7.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>CN(C)C=O>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][N:28]1[CH2:29][CH2:30][N:25]([C:20]2[N:19]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:26][CH2:27]1
Reactant: ClCc1ccc2ccccc2c1
Reactant: c1cnc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cnc(N2CCN(Cc3ccc4ccccc4c3)CC2)nc1

Procedure:
To a mixture containing 5.0 g. of β-chloromethylnaphthalene, 3.0 g. of sodium carbonate and 30 ml. of dimethylformamide is added 4.6 g. of pyrimidinylpiperazine. The mixture is stirred and heated on a steam bath for approximately two hours. The mixture is then cooled, filtered and the filtrate is concentrated to a small volume in vacuo. The residue is washed with water and crystallized from ethanol to yield 1-(β-napthylmethyl)-4-(2-pyrimidinyl)-piperazine having a melting point of 109°-110° C.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH:14]=O.[Cl-].[Li+].O>CN1CCN(C)C1=O>[CH2:14]([C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:1]=1[OH:8])[OH:7])[C:10]1[O:9][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccco1
Reactant: O=C1CCC(=O)CC1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: Oc1ccc(O)c(Cc2ccco2)c1
Temperature: 165 °C
Yield: 70.5 %

Procedure:
A mixture of 1,4-cyclohexanedione (5.6 g; 50 mmol), furan-2-carbaldehyde (4.8 g; 50 mmol) and anhydrous lithium chloride (2.1 g; 50 mmol) in 1,3-dimethyl-2-imidazolidinone (20 ml) was heated with stirring over an a oil bath at atmospheric pressure. The temperature of the bath was maintained at 165° C. for 1 h. The cooled reaction mixture was poured into water (300 ml) and extracted with ethyl acetate (2×150 ml). The combined organic layers were washed with water (2×100 ml), dried over magnesium sulphate and filtered. The organic solvent was removed in vacuo. The residue (9.4 g) was purified by flash chromatography using a silica gel column and toluene/ethyl acetate (90:10) as eluent, to give 6.7 g (70%) of 3-furfurylhydroquinone.