Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:18]1[CH:23]=[C:22]([O:24]C)[N:21]=[C:20]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28]2)[N:19]=1>Br.CC(O)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:18]1[N:19]=[C:20]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]2)[NH:21][C:22](=[O:24])[CH:23]=1
Reactant: COc1cc(-c2c[nH]c3ccc(-c4c(F)cccc4F)cc23)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)n1
Agent: Br
Solvent: CC(=O)O
Product: O=c1cc(-c2c[nH]c3ccc(-c4c(F)cccc4F)cc23)nc(N[C@@H]2CCCNC2)[nH]1
Yield: 22.4 %

Procedure:
A solution of (R)-tert-butyl 3-((4-(5-(2,6-difluorophenyl)-1H-indol-3-yl)-6-methoxypyrimidin-2-yl)amino)piperidine-1-carboxylate (0.17 g, 0.318 mmol) in 33% HBr in HOAc (3 mL) was heated at 90° C. for 14 h. The reaction was quenched with aq. NaHCO3 and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was washed with 50% EtOAc in petroleum ether to give (R)-6-(5-(2,6-difluorophenyl)-1H-indol-3-yl)-2-(piperidin-3-ylamino)pyrimidin-4(3H)-one (30 mg, 22%). MS (ESI, pos. ion) m/z: 422.1 (M+1); 1H-NMR (400 MHz DMSO-d6): δ ppm 11.78 (s, 1H), 8.48 (s, 1H), 8.13 (d, J=2.4 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.40-7.47 (m, 1H), 7.18-7.22 (m, 3H), 6.59 (brs, 1H), 6.00 (s, 1H), 3.93 (brs, 1H), 2.57 (s, 2H), 2.90 (d, J=9.2 Hz, 1H), 1.74 (brs, 1H), 1.50-1.53 (m, 2H), 1.18-1.22 (m, 3H).
Reaction SMILES: Br[CH2:2][CH2:3]Br.[Br:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([OH:13])[C:7]=1[OH:14].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:5][C:6]1[C:7]2[O:14][CH2:3][CH2:2][O:13][C:8]=2[CH:9]=[C:10]([Cl:12])[CH:11]=1
Reactant: Oc1cc(Cl)cc(Br)c1O
Reactant: BrCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: Clc1cc(Br)c2c(c1)OCCO2
Temperature: 25 °C

Procedure:
To a solution of 1,2-dibromoethane (1.44 ml, 16 mmol) and tetrabutylammonium bromide (96 mg, 2.5 mol %) in water (8 ml) at reflux under nitrogen was added a mixture of 3-bromo-5-chloro-benzene-1,2-diol (Preparation 27, 2.68 g, 12 mmol) and NaOH (1.06 g, 26.2 mmol) in water (10 ml) over 4 hours, and the resultant mixture stirred overnight. The reaction mixture was cooled to room temperature and diluted with water (100 ml). The mixture was extracted with diethyl ether (3×100 ml), and the combined organic extracts were concentrated in vacuo. Purification by flash chromatography, eluting with 90:10 pentane:dichloromethane, afforded the title compound as a yellow oil which crystallised upon standing to a yellow solid (1.78 g, 60% yield).
Reaction SMILES: CN1[CH2:24][CH2:23][C:5]2[N:6]([CH2:14][CH2:15][C:16]3[CH:17]=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[S:25]1CCC(=O)CC1>>[CH3:13][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:14][CH2:15][C:16]3[CH:17]=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=3)[C:5]3[CH2:23][CH2:24][S:25][CH2:3][C:4]=3[C:12]=2[CH:11]=1
Reactant: O=C1CCSCC1
Reactant: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(C)C1
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCSC1

Procedure:
The method was the same as for Dimebon, using tetrahydro-thiopyran-4-one in place of 1-methylpiperid-4-one. The desired product was isolated as a glassy yellow oil (13.1 mg, 8.7% over three steps based on 2-methyl-5-(N-nitroso-2-p-tolylaminoethyl)pyridine starting material) by column chromatography on SiO2, eluting with 4:1 EtOAc/MeOH.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]([C:13]([OH:15])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.S(Cl)([Cl:18])=O>>[OH:1][C:2]1[C:11]([CH3:12])=[C:10]([C:13]([Cl:18])=[O:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1c(O)nc2ccccc2c1C(=O)O
Reactant: O=S(Cl)Cl
Product: Cc1c(O)nc2ccccc2c1C(=O)Cl

Procedure:
A mixture of 2-hydroxy-3-methylquinoline-4-carboxylic acid (V, Step II, 5.11 g) and thionyl chloride (35 ml) is stirred at reflux for 3.5 hr. After cooling, the excess thionyl chloride is removed under reduced pressure. The residue is taken up in dichloromethane and taken to dryness again under reduced pressure. The dichloromethane addition/removal under reduced pressure is repeated twice. The residue is then dried under greatly reduced pressure for 1 hr to remove the last traces of thionyl chloride to give 2-hydroxy-3-methylquinolin-4-oyl chloride (V-A), which is taken up in 30 to 40 ml of dichloromethane and cooled at 0°. Triethylamine (3.50 ml) is added, followed by pyrrolidine (4.19 ml). After 5-10 min the ice bath is removed. After stirring for 3 hr, the mixture is partitioned between dichloromethane and aqueous sodium bicarbonate. The mixture is filtered through sodium sulfate and concentrated to a residue. The residue is chromatographed (silica gel; methanol/dichloromethane (4/96)) to give pyrrolidino 2-hydroxy-3-methylquinoline-4-carboxamide (VI), mp 175-176° which is crystallized from acetone, mp 223-227°.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:23](O)([CH3:26])([CH3:25])[CH3:24].N12CCCN=C1CCCCC2>CN(C)C=O.O>[C:23]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)O
Reactant: O=C(O)c1cccc(I)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)c1cccc(I)c1
Temperature: 40 °C
Yield: 92.1 %

Procedure:
To a solution of 3-iodobenzoic acid (50 g, 0.2 mol) in N,N-dimethylformamide (250 mL) was added solid 1,1′-carbonyldiimidazole (32.4 g, 0.2 mol) over 15 min. The resulting mixture was heated at 40° C. for 1 hr, then was added tert-butyl alcohol (29.6 g, 0.4 mol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (30.4 g, 0.2 mol) and heated at 40° C. overnight. The reaction was cooled to room temperature, diluted with water (500 mL) and extracted with hexane (2×500 mL). The combined organic layers were washed with water (2×400 mL), brine (250 mL), dried over anhydrous magnesium sulfate (15 g), filtered and concentrated under reduced pressure to give the title compound (56 g, 92%) as an oil. NMR 60 MHz, (CDCl3), δ 8.3 (m, 1H), 7.8 (m, 2H), 7.0 (m, 1H), 1.6 (s, 9H).
Reaction SMILES: [Si]([O:8][CH:9]([C:11]1[CH:12]=[CH:13][C:14]2[CH:25]=[CH:24][C:18]3=[N:19][CH:20]=[C:21]([Cl:23])[CH:22]=[C:17]3[C:16](=[O:26])[C:15]=2[CH:27]=1)[CH3:10])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:23][C:21]1[CH:22]=[C:17]2[C:16](=[O:26])[C:15]3[CH:27]=[C:11]([CH:9]([OH:8])[CH3:10])[CH:12]=[CH:13][C:14]=3[CH:25]=[CH:24][C:18]2=[N:19][CH:20]=1
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(O)c1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
7-(1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (20 mg, 0.05 mmol) was taken up in 1 mL of tetrahydrofuran. Tetrabutylammonium fluoride (0.06 mL of 1.0M in THF, 0.06 mmol) was added and the mixture was stirred at room temperature for 45 min. The reaction was concentrated in vacuo and directly purified via flash chromatography (silica, 0-35% ethyl acetate/hexanes) to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 8.80 (d, 1H); 8.50 (d, 1H); 8.23 (d, 1H); 7.76 (dd, 1H); 7.60 (d, 1H); 7.31 (d, 1H); 7.26 (d, 1H); 5.06 (q, 1H); 1.55 (d, 3H). Hydroxyl proton was not observed. LRMS (APCI) calc'd for (C16H13ClNO2) [M+H]+, 286.1; found 286.1.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([N:19]3[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])[O:21][C:20]3=[O:29])[CH:16]=2)[NH:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:30](N1C2C=CC=CC=2N=N1)=[O:31]>C1COCC1>[Si:1]([O:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([N:19]3[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])[O:21][C:20]3=[O:29])[CH:16]=2)[N:11]1[CH:30]=[O:31])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: O=Cn1nnc2ccccc21
Reactant: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CC(CO[Si](C)(C)C(C)(C)C)N3)C(=O)O1
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CC(CO[Si](C)(C)C(C)(C)C)N3C=O)C(=O)O1
Reaction time: 1 h
Yield: 88.9 %

Procedure:
A stirred mixture of the product from Step 9 (0.39 g, 0.93 mmol) and THF (15 ml), under nitrogen is treated with N-formylbenzotriazole (0.164 g, 1.12 mmol) and kept at ambient temperature for 1 h. It is then concentrated in vacuo. Chromatography of the residue on silica gel with mixtures of acetone-methylene chloride containing 20-40% acetone gave 0.37 g of the titled product: 1H NMR (300 MHz, CDCl3) δ0.00 (m, 6H), 0.73, 0.86 (s, s, 9H), 2.02 (s, 3H), 2.70, 3.23 (m, m, 2H), 3.68 (m, 5H), 4.03 (m, 1H), 4.43, 4.80 (m, m, 1H), 4.75 (m, 1H), 6.14 (m, 1H), 7.08, 7.20, 7.47, 7.61, 8.04 (m, 3H), 8.52, 8.86 (s, s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH:9]([C:12]([CH3:14])=O)([CH3:11])[CH3:10]>>[CH3:14][C:12]1[C:9]([CH3:11])([CH3:10])[C:7]2[C:2](=[CH:3][CH:4]=[C:5]([CH3:8])[CH:6]=2)[N:1]=1
Reactant: Cc1ccc(N)cc1
Reactant: CC(=O)C(C)C
Product: CC1=Nc2ccc(C)cc2C1(C)C
Yield: 87 %

Procedure:
p-Toluidine was reacted with methyl isopropyl ketone in the same way as in Example 3. 2,3,3,5-Tetramethyl-3-H-indole was formed in a yield of 87% of the theoretical yield.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][CH2:8][C:9](Cl)=[O:10].[CH3:12][O:13][N:14]([CH3:26])[C:15](=[O:25])[C:16]([CH3:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17]>C(Cl)Cl>[CH3:12][O:13][N:14]([CH3:26])[C:15](=[O:25])[C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:9](=[O:10])[CH2:8][CH2:7][CH2:6][Cl:5])=[CH:20][CH:19]=1)([CH3:24])[CH3:17]
Reactant: O=C(Cl)CCCCl
Reactant: CON(C)C(=O)C(C)(C)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CON(C)C(=O)C(C)(C)c1ccc(C(=O)CCCCl)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 62.6 %

Procedure:
Slurry AlCl3 (10.15 g, 76.1 mmol) and methylene chloride (45 mL) under a nitrogen atmosphere at room temperature. Add 4-chlorobutyryl chloride (4.27 mL, 38.1 mmol), stir for 20 minutes and add, by dropwise addition over 10 minutes, a solution of 2-methyl-2-phenyl-propionic acid, N-methoxy-N-methylamide (6.58 g, 31.7 mmol) in methylene chloride (15 mL). Stir at room temperature for 45 minutes, then heat at 30-35° C. for 7 hours. Pour into ice water (150 mL) and separate the layers. Wash the aqueous layer with water (3X75 mL), combine the aqueous layers and extract with methylene chloride (2X75 mL). Combine the organic layers and dry (Na2SO4). Filter, evaporate the filtrate in vacuo and purify by silica gel chromatography (3:1 hexane/ethyl acetate) give the title compound (6.19 g, 63%) as a light yellow oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:15]([O:19][C:20](=[O:24])[C@H:21]([CH3:23])[NH2:22])[CH:16]([CH3:18])[CH3:17]>>[CH2:15]([O:19][C:20](=[O:24])[C@H:21]([CH3:23])[NH:22][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:16]([CH3:18])[CH3:17]
Reactant: O=C(O)CCCCc1ccccc1
Reactant: CC(C)COC(=O)[C@H](C)N
Agent: Cl
Product: CC(C)COC(=O)[C@H](C)NC(=O)CCCCc1ccccc1

Procedure:
Following General Procedure BB and using 5-phenylpentanoic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10](O)=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([N:18](CC)CC)C.C(OC(Cl)=O)C(C)C.N.FC(F)(F)C(OC(=O)C(F)(F)F)=O>CO.C1COCC1.CCOC(C)=O.ClCCl>[C:10]([C@@H:9]1[CH2:13][CH2:14][CH2:15][N:8]1[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])#[N:18]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C#N
Temperature: -25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
To a flame dried flask was added 2 grams (9.3 mmols) of N-Boc proline followed by 93 ml, of dichloromethane and 4.24 grams (41.85 mmols) of triethylamine. The reaction mixture was then cooled to −25° C. and 2.5 grams (18.6 mmols) of iso-butylchloroformate was added dropwise. After stirring for 45 minutes at this low temperature, 0.83 grams (49 mmol) of ammonia was added to the reaction mixture as a 7N solution in methanol. The flask was allowed to warm to ambient temperature and stir for an additional 16 hours. After this time, the reaction mixture was evaporated to dryness and reconstituted in 200 mL of EtOAc. The organic layer was washed four 15 mL portions of 1N HCl, dried with MgSO4 and evaporated to dryness. The crude material was then immediately dehydrated to the nitrile according to general procedure E using 1.9 grams (18.88 mmols) of triethylamine and 2.34 grams (11.16 mmols) of trifluoroacetic anhydride in 93 mL of THF. After standard work-up and purification techniques (column chromatography, 25% EtOAc in hexanes), 0.91 grams (4.65 mmols, 50%) of the title product was recovered as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 4.53 (d, J=5.5 Hz, 0.5H), 4.48-4.38 (m, 0.5H), 3.57-3.41 (m, 1H), 3.41-3.22 (m, 1H), 2.31-1.92 (m, 4H), 1.47 (d, J=9.4 Hz, 9H). 13C NMR (75 MHz, CDCl3) δ 153.25, 119.38, 81.64, 47.39, 45.93, 31.86, 31.01, 28.52, 24.88, 24.04.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]CCC(O)=O.C[OH:15]>>[OH:15][C:3]1[CH:4]=[C:5]([CH3:6])[O:12][C:1](=[O:13])[CH:2]=1
Reactant: CO
Reactant: O=C(O)CCCCCCCC(=O)O
Product: Cc1cc(O)cc(=O)o1

Procedure:
Similar to Example 150, 6.81 g (21.9 mmol, 73%) of a methyl ester compound was obtained as orange crystals from 6.08 g (0.0 mmol recrystallized from 3 methanol) of monomethyl ester of azelaic acid and 3.78 g (30.0 mmol) of 4-hydroxy-6-methyl-2-pyrone by recrystallization from methanol.
Reaction SMILES: [C:1]12([C:11]([N:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16](=[O:23])[CH2:15][CH2:14]3)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[BH4-].[Na+]>CO>[C:1]12([C:11]([N:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]([OH:23])[CH2:15][CH2:14]3)=[O:12])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: O=C1CCN(C(=O)C23CC4CC(CC(C4)C2)C3)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(N1CCC(O)c2ccccc21)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C

Procedure:
A mixture of 0.6 g (1.94 mmol) 1-(Adamantane-1-carbonyl)-2,3-dihydro-1H-quinolin-4-one and 0.11 g (2.91 mmol) NaBH4 in 20 mL methanol was stirred at room temperature. The mixture was evaporated, taken up on isolute and subjected to column chromatography on silica eluting with a gradient formed from heptane and TBME to yield after evaporation of the product containing fractions 0.557 g (92%) as white solid. MS(m/e): 312.4 (MH+).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:25][CH2:24][C@@:12]34[C:13]5[C:18]6[CH2:19][C@@H:6]2[C@H:7]3[CH2:8][C@H:9]([C@:27]([OH:33])([C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:28])[C@H:10]([OH:26])[C@@H:11]4[O:23][C:14]=5[C:15]([OH:22])=[C:16]2[CH2:21][CH2:20][C:17]2=6)C[CH2:2]1.C(N1CC[C@@]23C4C5C[C@@H]1[C@H]2C[C@H]([C@](O)(C(C)(C)C)C)[C@H](OC)[C@@H]3OC=4C(O)=C1CCC1=5)C=C.C[C@@](O)(C(C)(C)C)[C@@H]1[C@]2(OC)[C@@H]3OC4=C(O)C=CC5=C4[C@]43CCN(CC3CC3)[C@H](C5)[C@@]4(CC2)C1>>[CH2:4]([N:5]1[CH2:25][CH2:24][C@@:12]23[C:13]4[C:18]5[CH2:19][C@@H:6]1[C@H:7]2[CH2:8][C@H:9]([C@:27]([OH:33])([C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:28])[C@H:10]([OH:26])[C@@H:11]3[O:23][C:14]=4[C:15]([OH:22])=[C:16]1[CH2:21][CH2:20][C:17]1=5)[CH:1]=[CH2:2]
Reactant: CC(C)(C)[C@@](C)(O)[C@H]1C[C@@H]2[C@H]3Cc4c5c(c(O)c6c4[C@@]2(CCN3CC2CC2)[C@@H](O6)[C@H]1O)CC5
Agent: C=CCN1CC[C@]23c4c5c6c(c(O)c4O[C@H]2[C@@H](OC)[C@@H]([C@](C)(O)C(C)(C)C)C[C@@H]3[C@H]1C5)CC6
Agent: CO[C@@]12CC[C@@]3(C[C@@H]1[C@](C)(O)C(C)(C)C)[C@H]1Cc4ccc(O)c5c4[C@@]3(CCN1CC1CC1)[C@H]2O5
Product: C=CCN1CC[C@]23c4c5c6c(c(O)c4O[C@H]2[C@@H](O)[C@@H]([C@](C)(O)C(C)(C)C)C[C@@H]3[C@H]1C5)CC6
Yield: 75.8 %

Procedure:
Compound 16 was synthesized similar to the procedure described in Example 1 for the preparation of compound 2 using compound 15 rather than compound 1. After column chromatography, 4.0 g of compound 16 (75.8%) was obtained with a purity of 98.5%.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.C(N(CC)CC)C.Cl[CH2:18][N:19]([C:26](=[O:28])[CH3:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[C:26]([N:19]([CH2:18][N:5]1[CH:4]=[C:3]([Cl:2])[CH:8]=[N:7][C:6]1=[O:9])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:28])[CH3:27]
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: CC(=O)N(CCl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(Cn1cc(Cl)cnc1=O)c1ccccc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
5-Chloropyrimidin-2-one hydrochloride (3.8 mmol) and triethylamine (7.6 mmol) was stirred together in CH2Cl2 (30 ml) for 10 minutes before a solution of N-chloromethyl acetanilide (see Preparation 16) (3.8 mmol) in CH2Cl2 (5 ml) was added. The mixture was stirred at 40° C. for 2 hours before the solvent was distilled off and the residue washed with water and ether. Yield 0.3 g, (28%) M.p. 150°-155° C. (decomp) (CH2Cl2 /pet. ether) 1H NMR (CDCl3, δ): 1.90 (CH3), 5.60 (CH2), 6.9-7.4 (Ph), 8.18 and 8.42 (H-4, H-6, J3Hz). IR (KBr) 1670-1680 cm-1 (CO).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:6][C:5](=[O:7])/[C:4](=[CH:8]/[C:9]([O:11][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)=[O:10])/[O:3]1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][C:2]1([CH3:29])[O:3][C:4](=[CH:8][C:9]([OH:11])=[O:10])[C:5](=[O:7])[O:6]1
Reactant: CC1(C)OC(=O)/C(=C/C(=O)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC1(C)OC(=O)C(=CC(=O)O)O1
Reaction time: 0.25 h
Yield: 95 %

Procedure:
A solution of the crude (Z)-2,2-dimethyl-5-(tert-butyldiphenylsilyloxycarbonyl methylene)-1,3-dioxolan-4-one (52.4 mmol) in tetrahydrofuran (200 ml) was treated with acetic acid (13 ml) followed with 50 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran. After 15 minutes at 22° C., the reaction mixture was filtered and the filtrate was concentrated in vacuo. Trituration of the residue with toluene gave 6.3 g (70% yield for three steps) of the title material as a white solid (>95% pure by 1HNMR).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:18]2[NH:34][C:21]3=[N:22][CH:23]=[C:24]([CH2:26][CH:27]4[CH2:31][O:30]C(C)(C)[O:28]4)[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>O1CCCC1>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:34][C:21]3=[N:22][CH:23]=[C:24]([CH2:26][CH:27]([OH:28])[CH2:31][OH:30])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OCC(Cc2cnc3[nH]c(C(CC4CCCC4)c4ccc(S(C)(=O)=O)cc4)cc3c2)O1
Agent: Cl
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(CC(O)CO)cnc3[nH]2)cc1
Temperature: 25 °C
Yield: 41.8 %

Procedure:
A mixture of 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-5-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (260 mg, 0.54 mmol) and 6N HCl (1.0 mL) in tetrahydrofuran (5 mL) was heated at reflux for 1 h. The mixture was cooled to room temperature and extracted with ethyl acetate and then washed with a saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) to afford 3-{2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-propane-1,2-diol (100 mg, 41.9%) as a white solid: LC/MS m/e calcd for C24H30N2O4S [M+H]+ 443.58, observed 443.2; 1H NMR (400 MHz, CDCl3) δ ppm 1.15 (m, 2H), 1.45 (m, 2H), 1.54-1.82 (m, 5H, H), 2.06 (m, 1H), 2.23 (m, 1H), 2.74 (dd, J=8.1, J=13.8 Hz, 1H), 2.82 (dd, J=4.8, J=13.8 Hz, 1H), 2.90 (br, 2H), 2.98 (s, 3H), 3.53 (dd, J=7.3, J=11.4 Hz, 1H), 3.68 (dd, J=3.0, J=11.4 Hz, 1H), 3.93 (m, 1H), 4.22 (t, J=7.7 Hz, 1H), 6.29 (s, 1H), 7.75 (d, J=8.3 Hz, 2H), 7.71 (s, 1H), 7.76 (s, 1H), 7.77 (d, J=8.3 Hz, 2 H), 10.82 (s, 1H).
Reaction SMILES: [CH:1]12[O:6][CH:5]1[CH2:4][N:3]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2]2.[F:14][C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1>>[C:10]([O:9][C:7]([N:3]1[CH2:2][C@@H:1]([C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)[C@H:5]([OH:6])[CH2:4]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Reactant: Fc1ccc([Mg]Br)cc1
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](c2ccc(F)cc2)C1

Procedure:
The title compound was prepared from tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate and 4-fluorophenylmagnesium bromide according to the procedure for Example 1, step A. 1H-NMR (CDCl3): δ: 1.49 (s, 9H), 3.2-3.4 (m, 3H), 3.50 (m, 1H), 3.7-3.95 (m, 2H), 4.32 (q, 1H, 5 Hz), 7.05 (t, 2H), 7.23 (m, 2H) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](Cl)=[O:29])[CH:20]=1>C1(C)C=CC=CC=1>[OH:12][C:3]1[C:2]([NH:1][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[C:25]([C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)[CH:26]=2)=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(N)c1O
Reactant: O=C(Cl)c1cccc(-c2cccnc2)c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1cccc(NC(=O)c2cccc(-c3cccnc3)c2)c1O
Temperature: 70 °C
Reaction time: 4 h
Yield: 89.1 %

Procedure:
Thionyl chloride (10 mL) was added to 3-(pyridin-3-yl)benzoic acid (1.5 g, 7.5 mmol) and the mixture was stirred under reflux overnight. The solvent was evaporated under reduced pressure and the residue was dried in vacuum giving 1.5 g crude 3-(pyridin-3-yl)benzoyl chloride. To a solution of methyl 3-amino-2-hydroxybenzoate (950 mg, 5.8 mmol) and pyridine (480 mg, 6 mmol) in toluene (50 mL) was added 3-(pyridin-3-yl)benzoyl chloride (1.5 g, 7 mmol) portion-wise at 0° C. and then stirred at 70° C. for 4 h. The resulting mixture was extracted with ethyl acetate (100 mL×4), the organic phase was washed with water and saturated sodium bicarbonate, dried with anhydrous sodium sulfate and evaporated under reduced pressure to obtain methyl 2-hydroxy-3-(3-(pyridin-3-yl)benzamido)benzoate as a yellow solid (1.8 g, yield 85%). LC-MS (ESI) m/z: 349 (M+1)+.
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[OH:7][C:6]1[CH:5]=[C:4]([CH2:3][CH2:2][C:1]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])[CH:11]=[CH:10][C:8]=1[OH:9]
Reactant: O=C(O)CCc1ccc(O)c(O)c1
Reactant: C1COCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Product: O=C(CCc1ccc(O)c(O)c1)N1CCOCC1
Reaction time: 8 h
Yield: 92.1 %

Procedure:
3 g of dihydrocaffeic acid and 1.43 g of morpholine were dissolved in 20 ml of DMF (dimethylformamide), and 202 mg of DMAP (dimethylaminopyridine) and 3.4 g of DCC (dicyclohexylcarbodiimide) were further added thereto under cooling, followed by allowing the mixture to stand overnight. The deposited dicyclohexyl urea was removed therefrom by filtration, and the resultant filtrate was then distilled off under reduced pressure. Afterward, the residue was washed with ether in order to obtain 3.8 g of N-[3-(3,4-dihydroxyphenyl)propionyl]morpholine in the state of light yellow crystals having a melting point of from 211° to 213° C.