Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([O:51][CH2:52][C@@H:53]3[CH2:55][C@H:54]3[C:56]([O:58][CH2:59][CH3:60])=[O:57])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.Cl.O1CCOCC1>C(Cl)Cl>[CH:1]1([N:4]([CH2:39][C:40]2[CH:41]=[C:42]([CH:43]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:45]=2)[O:51][CH2:52][C@@H:53]2[CH2:55][C@H:54]2[C:56]([O:58][CH2:59][CH3:60])=[O:57])[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:17][CH:18]=3)[CH2:11][CH2:10][NH:9][CH2:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCOC(=O)[C@@H]1C[C@H]1COc1cc(CCCOC)cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1C[C@H]1COc1cc(CCCOC)cc(CN(C(=O)[C@H]2CNCC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution tert-butyl (3R,4S)-3-({cyclopropyl[3-{[(1R,2R)-2-(ethoxy-carbonyl)cyclopropyl]methoxy}-5-(3-methoxypropyl)benzyl]amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-1-carboxylate (1 eq.) from the previous step in DCM (0.05 M) was added 4 M HCl in dioxane (10 eq.) and stirred at rt for 5 h. The reaction was concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 5% [2 M NH3 in MeOH] in DCM) to afford the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:24][C:23]3([CH2:26][CH2:25]3)[C:15]3[C:16]4[C:17](=[N:22][C:14]=3[CH:13]2[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[NH:18][CH:19]=[CH:20][CH:21]=4)=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:34]1(C)C=CC(S(OC)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:8][C:6]1[CH:5]=[C:4]([NH:9][C:10]([N:12]2[CH2:24][C:23]3([CH2:26][CH2:25]3)[C:15]3[C:16]4[C:17](=[N:22][C:14]=3[CH:13]2[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[N:18]([CH3:34])[CH:19]=[CH:20][CH:21]=4)=[O:11])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1cc(C)cc(NC(=O)N2CC3(CC3)c3c4ccc[nH]c-4nc3C2c2cccc(F)c2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc(C)cc(NC(=O)N2CC3(CC3)c3c4cccn(C)c-4nc3C2c2cccc(F)c2)c1

Procedure:
The compound (188 mg) prepared in Example 15 was suspended in toluene (8 mL) and methyl p-toluenesulfonate (0.32 mL) was added, followed by refluxing for 2 hours. After the reaction solution was air-cooled, an aqueous saturated sodium carbonate solution was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2→methylene chloride:methanol=85:15) to obtain the titled compound having the following physical properties (122 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:26]=[CH:25][C:11]([C:12]([NH:14][C@@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[CH2:16][OH:17])=[O:13])=[C:10]([F:27])[CH:9]=2)=[CH:6][C:5]([C@H:28]2[CH2:32][C@@H:31]([CH2:33][OH:34])[NH:30][CH2:29]2)=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[C:44](N1C=CN=C1)(N1C=CN=C1)=[O:45]>C(#N)C>[NH2:1][C:2]1[C:7]([C:8]2[CH:26]=[CH:25][C:11]([C:12]([NH:14][C@@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[CH2:16][OH:17])=[O:13])=[C:10]([F:27])[CH:9]=2)=[CH:6][C:5]([C@@H:28]2[CH2:29][N:30]3[C:44](=[O:45])[O:34][CH2:33][C@@H:31]3[CH2:32]2)=[CH:4][N:3]=1
Reactant: Nc1ncc([C@@H]2CN[C@H](CO)C2)cc1-c1ccc(C(=O)N[C@H](CO)c2cccc(Cl)c2)c(F)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc([C@H]2C[C@H]3COC(=O)N3C2)cc1-c1ccc(C(=O)N[C@H](CO)c2cccc(Cl)c2)c(F)c1
Reaction time: 1 h
Yield: 9.5 %

Procedure:
A solution of 4-(2-amino-5-((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)pyridin-3-yl)-N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide (20 mg, 0.041 mmol) (Example 7) and DIEA (72 μL, 0.412 mmol) in acetonitrile (0.5 mL) was treated with carbonyldiimidazole (8.0 mg, 0.049 mmol). After 1 h, the starting material was completely consumed. The reaction mixture was quenched with 1.0 N aqueous NaOH solution (1.0 mL) and the mixture was stirred vigorously for 5 min, then, diluted with DCM (10 mL). The organics were washed with brine (2 mL) and dried over Na2SO4 and concentrated. The crude material was purified by reverse phase prep HPLC yielding 4-(2-amino-5-((6R,7aS)-3-oxohexahydropyrrolo[1,2-c]oxazol-6-yl)pyridin-3-yl)-N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide (2.0 mg, 7% yield). LCMS (m/z): 511.3, 513.3 (MH+), 0.61 min; 1H NMR (400 MHz, CD3OD) δ ppm 7.92-7.84 (m, 2H), 7.46 (s, 1H), 7.44-7.40 (m, 1H), 7.38-7.35 (m, 1H), 7.34-7.28 (m, 1H), 5.19 (t, J=5.87 Hz, 1H), 4.61-4.56 (m, 1H), 4.34 (dd, J=3.52, 9.00 Hz, 1H), 4.24-4.15 (m, 1H), 3.92-3.80 (m, 1H), 3.74-3.62 (m, 1H), 2.41 (td, J=5.72, 11.64 Hz, 1H), 1.84-1.71 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH2:12][CH2:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH2:12][CH2:11][CH2:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: [H][H]
Reactant: N#Cc1ccc(C2=CCCc3cncn32)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C2CCCc3cncn32)cc1

Procedure:
A solution of 1.6 g of 5-p-cyanophenyl-7,8-dihydroimidazo[1,5-a]pyridine in 50 ml of ethyl acetate is hydrogenated at atmospheric pressure with 0.2 g of 5% palladium on charcoal until the theoretical uptake of hydrogen is complete. The catalyst is filtered, and the solvent evaporated to yield the title compound, m.p. 117°-118°.
Reaction SMILES: [CH3:1][C:2]([CH2:8][CH2:9][CH2:10][CH:11]([CH3:23])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:3][C:4]([O:6][CH3:7])=[O:5].[OH:24][CH2:25][CH:26](CO)[OH:27].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:1][C:2]([CH2:8][CH2:9][CH2:10][CH:11]([CH3:23])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:3][C:4]([O:6][CH2:7][CH:25]([CH2:26][OH:27])[OH:24])=[O:5]
Reactant: COC(=O)C=C(C)CCCC(C)CCCC(C)CCCC(C)C
Reactant: OCC(O)CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=CC(=O)OCC(O)CO)CCCC(C)CCCC(C)CCCC(C)C
Temperature: 100 °C
Reaction time: 12 h
Yield: 38.5 %

Procedure:
1.0 g (3.1 mmol) of methyl 3,7,11,15-tetramethylhexadec-2-enoate was added dropwise to a solution of 0.57 g (6.2 mmol) of glycerol and 0.85 g (6.2 mmol) of potassium carbonate in dry N,N-dimethylformamide (3 mL) at 80° C. After the reaction mixture was stirred at 100° C. for 12 hours, 1M hydrochloric acid was added. The resulting solution was extracted with ether, and the extract was washed with saturated sodium bicarbonate aqueous solution and saturated brine, successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane mixture) to obtain 459 mg of the title compound (35% yield) as a colorless viscous product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH3:17])[N:10]=2)[N:3]=1.[CH3:18][O-:19].[Na+].[Na].C(Cl)(Cl)Cl>CO>[CH3:18][O:19][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH3:17])[N:10]=2)[N:3]=1
Reactant: C[O-]
Reactant: CCCc1cccc(-c2nc(C)cc(Cl)n2)n1
Agent: [Na+]
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCc1cccc(-c2nc(C)cc(OC)n2)n1
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 4-chloro-6-methyl-2-(6-n-propyl-2-pyridinyl)pyrimidine (1 g) in methanol (10 ml), was added sodium methoxide prepared from methanol (10 ml) and metallic sodium (0.11 g). After being left to stand at room temperature for two hours, the solution was concentrated under reduced pressure. To the residue obtained, was added chloroform (100 ml). The mixture was washed twice with water (30 ml each) and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure to obtain 4-methoxy-6-methyl-2-(6-n-propyl-2-pyridinyl)pyrimidine (0.93 g, yield: 95 %).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][O:6][C:5]2[CH:8]=[CH:9][S:10][C:4]=2[CH:3]1[NH:11][C:12](=[O:23])[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1.[N+:24]([O-])([OH:26])=[O:25].[K+].[Br-]>C(O)(=O)C>[OH:1][CH:2]1[CH2:7][O:6][C:5]2[CH:8]=[C:9]([N+:24]([O-:26])=[O:25])[S:10][C:4]=2[CH:3]1[NH:11][C:12](=[O:23])[C:13]1[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:18]=1
Reactant: O=C(NC1c2sccc2OCC1O)c1ccc(C(F)(F)F)cc1
Reactant: O=[N+]([O-])O
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)O
Product: O=C(NC1c2sc([N+](=O)[O-])cc2OCC1O)c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared as described in Example 9 starting with 5,6-dihydro-6-hydroxy-7-(4-trifluoromethylbenzamido)-7H-thieno[3,2-b]pyran (1.5 g, 4.04 mmol) and 90% nitric acid (2.5 mL) in acetic acid (20 mL) to give a yellow solid, 0.165 g (10%): mp 219°-220° C.; IR (KBr): 3310, 1661, 1538 and 1504 cm-1 ; MS: m/z 417 (MH+); 1H NMR (DMSO-d6): δ 1.26 (s, 3H), 1.45 (s, 3H), 3.92 (m, 1H, simplifies to d, J=8.9 Hz, with D2O), 4.98 (m, 1H, simplifies to d, J=8.9 Hz, with D2O), 5.99 (d, 1H, exchanges with D2O), 7.74 (s, 1H), 7.92 (d, J=8.5 Hz, 2H), 8.12 (d, J=8.5 Hz, 2H) and 9.30 (d, 1H, exchanges with D2O).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][CH:9]1[CH2:14][CH2:13][C:12]([C:15]2[CH:20]=[C:19]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28]([C:30]2[NH:31][CH:32]=[C:33]([C:35]#[N:36])[N:34]=2)=[O:29])=[CH:11][CH2:10]1.[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH:43]=O>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][CH:9]1[CH2:14][CH2:13][C:12]([C:15]2[CH:20]=[C:19]([CH:21]3[CH2:22][CH2:23][N:24]([CH2:43][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][N:37]=4)[CH2:25][CH2:26]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28]([C:30]2[NH:31][CH:32]=[C:33]([C:35]#[N:36])[N:34]=2)=[O:29])=[CH:11][CH2:10]1
Reactant: O=Cc1ccccn1
Reactant: CC1CC=C(c2cc(C3CCNCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC1CC=C(c2cc(C3CCN(Cc4ccccn4)CC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1

Procedure:
This compound was prepared according to the procedure in Example 21 from 4-cyano-1H-imidazole-2-carboxylic acid [2-(4-methyl-cyclohex-1-enyl)-4-piperidin-4-yl-phenyl]-amide (as prepared in Example 17) and pyridine-2-carbaldehyde. 1H-NMR (400 MHz, DMSO-d6): δ 14.25 (br s, 1H), 9.90 (br s, 1H), 9.79 (s, 1H), 8.72 (s, 1H), 8.36 (s, 1H), 7.98 (m, 1H), 7.86 (dd, 1H), 7.54 (d, 1H), 7.52 (m, 1H), 7.20 (m, 1H), 7.12 (d, 1H), 5.74 (m, 1H), 4.56 (s, 2H), 3.40 (m, 2H), 3.18 (m, 2H), 2.88 (m, 1H), 2.48-2.22 (m, 3H), 2.18-2.06 (m, 4H), 1.98-1.82 (m, 3H), 1.52 (m, 1H), 1.02 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C28H32N6O, 481.2 (M+H). found 481.2.
Reaction SMILES: [NH2:1][C@H:2]([CH2:12][F:13])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)[OH:4].[CH3:14][C:15]([CH3:17])=O>>[F:13][CH2:12][C@@H:2]1[C@@H:3]([C:5]2[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=2)[O:4][C:15]([CH3:17])([CH3:14])[NH:1]1
Reactant: N[C@H](CF)[C@H](O)c1ccc(I)cc1
Reactant: CC(C)=O
Product: CC1(C)N[C@H](CF)[C@@H](c2ccc(I)cc2)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetone (150 mL) is added to commercially available (1R,2S)-2-amino-3-fluoro-1-(4-iodophenyl)propan-1-ol (15.0 g, 50.8 mmol). After stirring overnight at room temperature the solvent is removed under reduced pressure to give the title compound (17.6 g): m/z (Cl) M+H 335.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](I)=[C:9]([C@@H:11]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:12])[N:10]=2)[CH:7]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1.[F-].[Cs+].O>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:27]3[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=3)=[C:9]([C@@H:11]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:12])[N:10]=2)[CH:7]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)c1nc2ccc(F)cn2c1I
Reactant: OB(O)c1cccnc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](NC(=O)OCc1ccccc1)c1nc2ccc(F)cn2c1-c1cccnc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-benzyl (1-(6-fluoro-3-iodoimidazo[1,2-a]pyridine-2-yl)ethyl)carbamate (100 mg, 0.22 mmol) and pyridine 3-yl-boronic acid (30.7 mg, 0.25 mmol) in 1,4-dioxane (2 mL) was added cesium fluoride (66.8 mg, 0.440 mmol) at 25° C. The reaction mixture was degassed with nitrogen for 30 min and then tetrakis triphenylphosphine palladium(0) (13 mg, 0.011 mmol) was added at 25° C. The reaction mixture was stirred overnight at 100° C. After completion of the reaction water was added and the mixture extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography using silica gel (100-200 mesh) and 0-4% MeOH in DCM to provide (S)-Benzyl (1-(6-fluoro-3-(pyridine-3-yl)imidazo[1,2-a]pyridine-2-yl)ethyl)carbamate: LC-MS (ESI)] m/z 391.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([S:7]([C:10]1[CH:14]=[CH:13][O:12][C:11]=1[CH3:15])(=[O:9])=[O:8])[CH3:6])[CH3:2].Cl[CH2:18][C:19]1[CH:33]=[CH:32][C:22]([O:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:21][CH:20]=1>>[CH2:1]([O:3][C:4](=[O:16])[C:5]([CH3:6])([S:7]([C:10]1[CH:14]=[CH:13][O:12][C:11]=1[CH3:15])(=[O:8])=[O:9])[CH2:18][C:19]1[CH:33]=[CH:32][C:22]([O:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:21][CH:20]=1)[CH3:2]
Reactant: ClCc1ccc(OCCN2CCCCC2)cc1
Reactant: CCOC(=O)C(C)S(=O)(=O)c1ccoc1C
Product: CCOC(=O)C(C)(Cc1ccc(OCCN2CCCCC2)cc1)S(=O)(=O)c1ccoc1C

Procedure:
2-Methyl-2-(2-methyl-furan-3-sulfonyl)-3-[4-(2-piperidin-yl-ethoxy)-phenyl]-propionic acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from 2-(2-methyl-furan-3-sulfonyl)-propionic acid ethyl ester (2.4 g, 9.8 mmol) and 1-[2-(4-chloromethylphenoxy)-ethyl]-piperidine (2.96 g, 10.7 mmol); Yield 2.4 g (92%); amber oil; MS 464.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=2)=[N:7][CH:6]=1)[CH3:2].COC(OC)OC.[CH2:28]([NH2:36])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[BH4-].[Na+]>CO>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][NH:36][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)=[N:7][CH:6]=1)[CH3:2]
Reactant: NCCc1ccccc1
Reactant: CCOC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: CCOC(=O)c1ccc(Oc2ccc(CNCCc3ccccc3)cc2)nc1
Reaction time: 3.5 h
Yield: 110.1 %

Procedure:
Combine 6-(4-Formyl-phenoxy)-nicotinic acid ethyl ester (0.62 g, 2.29 mmol), MeOH (12 mL), Trimethylorthoformate (8 mL), and Phenethylamine (0.26 mL, 2.06 mmol). After the reaction stirs at room temperature under a Nitrogen atmosphere for 3.5 hours, add NaBH4 (251.0 mg, 2.75 mmol). After the reaction stirs at room temperature for 12 hours, concentrate under reduced pressure and add the mixture to a 5 g SCX column. Wash the column with MeOH and elute with 1N NH3 MeOH to afford 854.0 mg (99% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 2.8 (2H, t), 2.8-3.0 (4H, m), 3.8 (2H, s), 3.9 (3H, s), 6.9 (1H, d), 7.1-7.4 (9H, m), 8.3 (1H, d), 8.8 (1H, s); MS m/z 377 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([CH3:15])[C:9]=2[CH3:16])=[O:5])[CH3:2].[C:17]([O:21][C:22]([N:24]1[CH2:28][C@H:27]([CH3:29])OS1(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:27]([CH3:29])[CH2:28][NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([CH3:15])[C:9]=2[CH3:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(C)c(C)c2[nH]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Product: CCOC(=O)c1cc2ccc(C)c(C)c2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
The title compound, ISP-MS: m/e=375.4 (M+H+), was prepared in accordance with the general method of example 12b) from 6,7-dimethyl-1H-indole-2-carboxylic acid ethyl ester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]1[CH2:32][O:31][C:3]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([CH2:4][CH2:5][C@H:6]2[CH:10]=[CH:9][C:8](=[O:11])[C@@H:7]2[CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[O:2]1.[C:33](C1C=CC=CC=1)(=[O:40])C1C=CC=CC=1>CO>[CH:21]([O:20][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][CH:14]=[CH:13][CH2:12][C@H:7]1[C:8](=[O:11])[CH2:9][C@@H:10]([CH2:33][OH:40])[C@@H:6]1[CH2:5][CH2:4][C:3]1([O:2][CH2:1][CH2:32][O:31]1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([CH3:22])[CH3:23]
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: CCCCCCCC1(CC[C@H]2C=CC(=O)[C@@H]2C/C=C\CCCC(=O)OC(C)C)OCCO1
Solvent: CO
Product: CCCCCCCC1(CC[C@H]2[C@H](CO)CC(=O)[C@@H]2CC=CCCCC(=O)OC(C)C)OCCO1

Procedure:
Isopropyl (Z)-7-[(1R,2S)-2-(3,3-ethylenedioxydecyl)-5-oxo-cyclopent-3-enyl]hept-5-enoate (3) (0.81 g) and benzophenone were dissolved in methanol. Under argon atmosphere, the solution was irradiated with 300-W high-pressure mercury lamp for 4 hours and 40 minutes. After evaporation of the solvent, the crude product was chromatographed on silica gel (n-hexane/ethyl acetate=3/2) to give isopropyl-7-[(1R,2S,3R)-2-(3,3-ethylenedioxydecyl)-3-hydroxymethyl-5-oxocyclopentyl]hept-5-enoate (4). Yield 0.41 g, 47%.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1)[CH3:2].[NH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[CH:14]2.C(O)(=O)C.C(=O)([O-])O.[Na+]>CO>[CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([NH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCC(=O)CC1
Reactant: Nc1ccc2[nH]ncc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCN1CCC(Nc2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.7 %

Procedure:
1-Ethyl-4-piperidone (76 mg), 5-aminoindazole (67 mg), and acetic acid (0.02 ml) were dissolved in methanol (1 ml), and a borane-pyridine complex (0.06 ml) was added dropwise to the solution at room temperature. The reaction-mixture was stirred at room temperature for 18 hr. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was then added thereto, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC [chloroform/methanol] to give the title compound (50 mg, yield 41%).
Reaction SMILES: [C:1](OC(C)(C)C)(=[O:6])[CH2:2][C:3]([CH3:5])=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1)[NH2:17].CS(O)(=O)=O.O>C1(C)C(C)=CC=CC=1>[CH3:22][O:21][C:19]1[CH:20]=[C:14]([O:13][CH3:12])[CH:15]=[C:16]2[C:18]=1[C:3]([CH3:5])=[CH:2][C:1](=[O:6])[NH:17]2
Reactant: COc1cc(N)cc(OC)c1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: CS(=O)(=O)O
Solvent: O
Solvent: Cc1ccccc1C
Product: COc1cc(OC)c2c(C)cc(=O)[nH]c2c1
Temperature: 125 °C
Reaction time: 0.17 h

Procedure:
tert-Butyl acetoacetate (1.58 g) was heated to 120° C. and 3,5-dimethoxyaniline (1.53 g) dissolved in xylene (4 ml) was added. The mixture was heated at 120-130° C. for 20 minutes and then cooled to room temperature. Methanesulfonic acid (2 ml) was added and the mixture was stirred at ambient temperature for 10 minutes. Water (40 ml) was added and the precipitate filtered and dried. Yield 1.31 g (60%).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.O>ClCCCl>[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12][NH:6][C:5]1[CH:7]=[CH:8][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: Nc1ccc(I)cc1
Reactant: O=Cc1ccccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: O
Solvent: ClCCCl
Product: Fc1ccccc1CNc1ccc(I)cc1
Yield: 109.5 %

Procedure:
A solution of 4-iodoaniline (1 g, 4.5 mmol), 2-fluorobenzaldehyde (0.48 ml, 0.566 g, 4.5 mmol) and triacetoxyborohydride (1.9 g, 9.0 mmol) in 1,2-dichloroethane (20 ml) was stirred for 4 days at room temperature. After addition of water the mixture was extracted with DCM. The combined organic layers were dried (Na2SO4), filtered and evaporated to give the title compound (1.612 g, quant.). The crude material was used without further purification. MS: (ES/+) m/z: 328 [MH+], C13H11FIN requires 327; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.4-7.1 (m, 6H), 6.4 (d, 2H), 4.3 (m, 1H), 2.5 (m, 2H).
Reaction SMILES: O1CCCC1.[C:6]([O:10][C:11]([NH:13][C@:14]12[CH2:22][CH:21]1[CH2:20][C@H:19]1[C@@H:15]2[CH2:16][N:17]([C:23](=O)[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH2:18]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[OH-].[Na+]>O>[C:6]([O:10][C:11]([NH:13][C@:14]12[CH2:22][CH:21]1[CH2:20][C@H:19]1[C@@H:15]2[CH2:16][N:17]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[CH2:18]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: COc1ccc(C(=O)N2C[C@H]3CC4C[C@]4(NC(=O)OC(C)(C)C)[C@H]3C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN2C[C@H]3CC4C[C@]4(NC(=O)OC(C)(C)C)[C@H]3C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
A 1M tetrahydrofuran solution (7.0 ml) of a boranetetrahydrofuran complex (7.0 mmol) was added dropwise to a tetrahydrofuran (20 ml) solution of (1R,2R,6S)-1-t-butoxycarbonylamino-4-p-anisoyl-4-azatricyclo[6.1.0.02,6]nonane (970 ml, 2.60 mmol) while cooling with ice, and the mixture was stirred at room temperature for 1 hour. While cooling with ice, water was added to the reaction mixture to decompose the excess borane-tetrahydrofuran complex. A 1N sodium hydroxide aqueous solution (10 ml) was added thereto, followed by refluxing for 6 hours. After cooling to room temperature, the reaction mixture was extracted with diethyl ether. The extract was dried over anhydrous sodium sulfate, the solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to give 453 mg (1.26 mmol, 48%) of the title compound as a colorless oily substance.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[CH:19]=1.[O:21]1[CH2:24][C:23](=[O:25])[CH2:22]1>C1COCC1>[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:20])[C:19]=1[C:23]1([OH:25])[CH2:24][O:21][CH2:22]1
Reactant: O=C1COC1
Reactant: Fc1cncc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: OC1(c2c(F)cncc2Br)COC1
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 84.5 %

Procedure:
n-BuLi (1.6 M in hexane, 4.26 mL, 6.82 mmol) was added dropwise to a solution of diisopropylamine (1.05 mL, 7.39 mmol) in THF (14 mL) at −78° C. under Nitrogen atmosphere. The resulting mixture was warmed up to −40° C. and stirred for 10 min and recooled to −78° C. A solution of 3-bromo-5-fluoropyridine (1000 mg, 5.68 mmol) in THF (5 mL) was added dropwise at this temperature. After completion of addition, the reaction mixture turned brown. After 30 min, Oxetan-3-one (491 mg, 6.82 mmol) was added dropwise and the resulting mixture was stirred for 30 min at this temperature. The reaction was quenched with saturated NH4Cl solution. The mixture was extracted with ethyl acetate, and the combined extracts were washed with saturated NaHCO3 solution, dried over Na2SO4 and filtered. After concentration, 3-(3-Bromo-5-fluoro-pyridin-4-yl)-oxetan-3-ol (1190 mg, 84%) was obtained as a dark red solid; ESI-MS m/z: 249 [M+1]+, Retention time 0.83 min; 1H-NMR (MeOD, 400 MHz) δ 4.77 (d, J=8.8 Hz, 2H), 5.25 (d, J=8.8 Hz, 1H), 5.26 (d, J=8.8 Hz, 1H), 8.45 (d, J=1.6 Hz, 1H), 8.56 (s, 1H).