Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:12]([OH:14])=[O:13])[NH:7]2.C1CCN2C(=NCCC2)CC1.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:12]([O:14][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:13])[NH:7]2
Reactant: COc1cccc2[nH]c(C(=O)O)cc12
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cccc2[nH]c(C(=O)OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
2.65 g of 4-methoxyindole-2-carboxylic acid are dissolved in 15 ml of DMF, 2.11 g of DBU are added and the mixture is then stirred at RT for 1 hour. 2.61 g of benzyl bromide are added dropwise at RT and this mixture is stirred for 5 hours at RT. The mixture is concentrated under vacuum and the residue is taken up in EtOAc, washed with water, with saturated Na2CO3 solution, with sulphate buffer and then with saturated aqueous NaCl. This solution is dried over Na2SO4 and concentrated. 3.57 g of the expected compound are obtained, which product crystallizes from pentane: m.p.=162-164° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH2:15][CH2:14][CH2:13][C:8]3=[N:9][NH:10][C:11]([CH:12]=1)=[C:7]23)([O-:3])=[O:2].[O-]CC.[Na+].[CH2:20]1[O:23][CH:21]1[CH3:22].[Cl-].[NH4+]>C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[CH2:15][CH2:14][CH2:13][C:8]3=[N:9][N:10]([CH2:20][CH:21]([OH:23])[CH3:22])[C:11]([CH:12]=1)=[C:7]23)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc2c3c(n[nH]c3c1)CCC2
Reactant: CC1CO1
Agent: CC[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC(O)Cn1nc2c3c(cc([N+](=O)[O-])cc31)CCC2
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To a solution of the product from Step B (4.85 g, 23.9 mmol) in ethanol (50 mL) was added sodium ethoxide (14.2 mL, 35.0 mmol, 21% solution in ethanol) at room temperature. After 30 min, propylene oxide (4.14 mL, 47.8 mmol) was added, and the resultant solution was stirred for 18 h at room temperature. A saturated aqueous ammonium chloride solution (20 mL) was added to the reaction mixture and the ethanol was evaporated. This mixture was extracted with ethyl acetate (3×65 mL) and the combined extracts were washed with brine (30 mL), dried (MgSO4), and evaporated. The residue was purified by column chromatography (silica, 50% to 80% gradient of ethyl acetate in hexane) to yield the desired product as a solid (2.0 g, 32%): m.p: 147-148° C.; MS (ES) m/z 262 (M+); 1H NMR (CDCl3) δ 8.17 (1H, s), 7.74 (1H, s), 4.31 (3H, m), 3.05 (4H, 2d, J=6.0 Hz), 2.19 (4H, m), 1.30 (3H, t, J=6.0 Hz). The regioisomer formed during the alkylation was also isolated as a solid (1.4 g, 22%): mp 140-141° C.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[OH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH:17]=[O:18]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH2:1]([O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH:17]=[O:18])[CH:3]1[O:5][CH2:4]1
Reactant: ClCC1CO1
Reactant: O=Cc1c(O)ccc2ccccc12
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: O=Cc1c(OCC2CO2)ccc2ccccc12
Yield: 71 %

Procedure:
As shown in Chemical Formula 2, in 196 mL (2.47 mol) of epichlorohydrin (2), 17.1 g (99.0 mmol) of 2-hydroxy-1-naphthoaldehyde (1) was dissolved and thereto, 2.26 g (9.92 mmol) of benzyltriethylammonium chloride was added, followed by refluxing the resultant reaction mixture for 15 minutes to effect the reaction. Then, the reaction solution was dissolved in 200 mL of chloroform and the resultant solution was washed with 150 mL of water three times. The organic phase was dried over MgSO4 (magnesium sulfate), and the solvent thereof was concentrated under reduced pressure. The resultant residue was recrystallized in isopropyl alcohol and the resultant needle crystal was washed with isopropyl alcohol to obtain 16.1 g (yield: 71%) of 2-(glycidyloxy)-1-naphthoaldehyde (3) as a needle crystal.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C@@H:21]([NH2:23])[CH3:22])=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=CC1=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>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C@@H:21]([NH:23][C:10]([C@H:9]2[CH2:13][CH2:14][CH2:15][N:8]2[C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])=[O:12])[CH3:22])=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Reactant: C[C@H](N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)[C@H]1CCCN1C(=O)OC(C)(C)C)c1ccc(Cl)cc1

Procedure:
Boc-D-Proline (4.3 g, 20 mmol) was dissolved in DMF (100 ml). Then (S)-4-Chloro-α-methybenzylamine (3 ml, 22 mmol) and HBTU (7.58 g, 20 mmol), DIEA (6.96 ml, 40 mmol) were added while stirring. The reaction mixture was stirred overnight. The reaction mixture was diluted with EtOAc (100 ml), washed with 1N HCl (2×50 ml), sat. aq. NaHCO3 (2×50 ml) and brine, dried over Na2SO4, and concentrated in vacuo. The crude desired product as a white solid (6 g, 85.7%) directly used for next step.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:14](=O)([O-])[O-:15].[Na+].[Na+]>C(OC)=O.CN(C=O)C>[OH:15][CH:14]=[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: COC=O
Solvent: CN(C)C=O
Product: COC(=O)C(=CO)c1ccccc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A solution of methyl phenylacetate (16.03g) in methyl formate (132ml) and dry DMF (100 ml) was added dropwise over 40 minutes to a stirred suspension of sodium hydride (5.14g) in dry DMF (200ml) at between 0° and 5° C. (effervescence and foaming). The resulting mixture was stirred at about -5° C. for 30 minutes, diluted with dry DMF (250ml), then allowed to warm and stir at room temperature for 3 hours. Ice and sodium carbonate were added to the mixture and it was washed with ether (x2), then acidified with concentrated hydrochloric acid and extracted with ether (x4). The extracts were washed with water (x3), treated with magnesium sulphate and charcoal, filtered and concentrated to give methyl 3-hydroxy-2-phenylpropenoate (13.56g, 71%) as a solid, m.p. 33.5°-35.5° C., which was used for the subsequent steps without further purification.
Reaction SMILES: C(N(CCCC)CCCC)CCC.[CH2:14]([OH:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17].[CH2:23]=[C:24]([C:29](OS(F)(=O)=O)([F:31])[F:30])[C:25]([F:28])([F:27])[F:26]>COCCOCCOC>[CH2:23]=[C:24]([C:29]([O:22][CH2:14][C:15]([C:16]([F:19])([F:18])[F:17])([F:21])[F:20])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26]
Reactant: C=C(C(F)(F)F)C(F)(F)OS(=O)(=O)F
Reactant: OCC(F)(F)C(F)(F)F
Solvent: CCCCN(CCCC)CCCC
Solvent: COCCOCCOC
Product: C=C(C(F)(F)F)C(F)(F)OCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 116.2 %

Procedure:
A 100 ml flask is charged with tributylamine (15 g) and diglyme (20 ml) in a dry box. 1,1,-Dihydroperfluoropropanol (24.0 g) is added. CH2═C(CF3)CF2OSO2F (19.5 g) is added dropwise at 0-5° C. The resulting mixture is stirred at room temperature for 3 hours. The mixture is then distilled to give a liquid, which is redistilled (spinning band column) giving 27.3 g CH2═C(CF3)CF2OCH2CF2CF3, b.pt. 54° C. at 200 mm Hg. Yield is 58%. Less pure fractions are not included in the yield calculation.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[NH:21][C:22]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([Cl:30])[CH:25]=2)=[O:23])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>ClCCl>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[Cl:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][N:27]=1)[C:22]([NH:21][C:15]1[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=1[N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)ccc2NC(=O)c2ccnc(Cl)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)cc1N1CCNCC1)c1ccnc(Cl)c1

Procedure:
A solution of 4-{5-chloro-2-[(2-chloro-pyridine-4-carbonyl)-amino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (6.7 g, Example 1, Step C) in dichloromethane (20 ml) was treated with trifluoroacetic acid (10 ml) for 20 hours at room temperature. Concentration of the solution under reduced pressure afforded 2-chloro-N-[4-chloro-2-(piperazin-1-yl)-phenyl]-isonicotinamide trifluoroacetate (6.9 g) as a brown solid. MS (ES+) 351/353 (M+H+).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([O:11][C:12]([N:14]2[CH2:18][C@@H:17]([N:19]([CH2:32][C:33]3[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([C:43]([F:46])([F:45])[F:44])[CH:34]=3)[C:20]3[N:25]=[CH:24][C:23]([C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)=[CH:22][N:21]=3)[CH2:16][C@H:15]2[CH2:47][CH3:48])=[O:13])[CH:8]=[CH:9][CH:10]=1)=[O:4].Cl.O1CCOCC1>O.CCOCC>[C:3]([C:5]1[CH:6]=[C:7]([O:11][C:12]([N:14]2[CH2:18][C@@H:17]([N:19]([CH2:32][C:33]3[CH:34]=[C:35]([C:43]([F:44])([F:45])[F:46])[CH:36]=[C:37]([C:39]([F:41])([F:42])[F:40])[CH:38]=3)[C:20]3[N:25]=[CH:24][C:23]([C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)=[CH:22][N:21]=3)[CH2:16][C@H:15]2[CH2:47][CH3:48])=[O:13])[CH:8]=[CH:9][CH:10]=1)([OH:4])=[O:2]
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1C(=O)Oc1cccc(C(=O)OC)c1
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1C(=O)Oc1cccc(C(=O)O)c1
Temperature: 100 °C
Reaction time: 19 h
Yield: 32.6 %

Procedure:
A mixture of (2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid 3-methoxycarbonylphenyl ester (0.037 mmol; 25 mg), aqueous 6M HCl (0.5 mL) and 1,4-dioxane (0.1 mL) is stirred at 100° C. for 19 hours. The mixture is cooled to ambient temperature, then diluted with water and Et2O. The product is extracted three times with Et2O. The combined organic layer is washed with brine, dried over Na2SO4, filtered, concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: dichloromethane/methanol) to give (2R,4S)-4-{(3,5-Bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid 3-carboxy-phenyl ester (8.0 mg, 33%); ESI-MS m/z: 663 [M+1]+, Retention time 2.14 min (condition A).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:14]2[CH:13]=[CH:12][S:11][C:10]=2[C:9]([OH:15])=[CH:8][CH:7]=1.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27].[H-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:14]2[CH:13]=[CH:12][S:11][C:10]=2[C:9]([O:15][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:8][CH:7]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: CCOC(Cc1ccc(O)c2sccc12)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(Cc1ccc(OCc2nc(-c3ccccc3)oc2C)c2sccc12)C(=O)OC

Procedure:
In analogy to the procedure described in example 108 c], [rac]-2-ethoxy-3-(7-hydroxy-benzo[b]thiophen-4-yl)-propionic acid methyl ester was treated with 4-chloromethyl-5-methyl-2-phenyloxazole and sodium hydride in N,N-dimethylformamide to yield [rac]-2-ethoxy-3-[7-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzo[b]thiophen-4yl]-propionic acid methyl ester, which was further saponified in analogy to the procedure described in example 91 e] to yield [rac]-2-ethoxy-3-[7-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzo[b]thiophen-4-yl]-propionic acid as colorless solid.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[C:22]([F:29])[CH:21]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[C:22]([F:29])[CH:21]=1
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(Cl)cc4F)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (66 mg, 75%), MS (ISP) m/z=354.5 [(M+H)+], mp 270° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 4-chloro-2-fluoro-phenylboronic acid (56.7 mg, 0.325 mmol).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C@@H:16]([C:34]([OH:36])=[O:35])[CH2:17][C:18]3[CH:23]=[C:22]([CH3:24])[C:21]([O:25]CC4C=CC=CC=4)=[C:20]([CH3:33])[CH:19]=3)=[O:14])[CH2:9][CH2:8]2)[N:5]=[C:4]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[NH:3]1.C1COCC1>C(Cl)Cl.[Pd]>[O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C@@H:16]([C:34]([OH:36])=[O:35])[CH2:17][C:18]3[CH:23]=[C:22]([CH3:24])[C:21]([OH:25])=[C:20]([CH3:33])[CH:19]=3)=[O:14])[CH2:9][CH2:8]2)[N:5]=[C:4]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(n3nc(-c4ccccc4)[nH]c3=O)CC2)C(=O)O)cc(C)c1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(n3nc(-c4ccccc4)[nH]c3=O)CC2)C(=O)O)cc(C)c1O
Reaction time: 12 h

Procedure:
A solution of 2.50 g (4.38 mmol) (R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carboxylate in 50 mL DCM was combined with 250 mg 10% Pd/C and hydrogenated at RT under a hydrogen pressure of 3000 hP for 4.5 h. To complete the reaction a further 250 mg catalyst were added, the mixture was hydrogenated for 12 h at 40° C., combined with 25 mL THF and 250 mg catalyst and hydrogenated for a further 12 h at 40° C. The catalyst was suction filtered and the filtrate was evaporated down i.vac. The residue was stirred with DIPE, suction filtered and dried.
Reaction SMILES: [CH3:1][Si:2]([CH3:38])([CH3:37])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:20][CH:19]=2)[CH:9]=1.C1C(=O)N([I:46])C(=O)C1>C(#N)C>[CH3:34][Si:33]([CH3:36])([CH3:35])[CH2:32][CH2:31][O:30][CH2:29][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:37])[CH3:38])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([I:46])=[C:12]2[N:11]=[C:10]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:20][CH:19]=2)[CH:9]=1
Reactant: COC(=O)Cc1ccc(Oc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: COC(=O)Cc1ccc(Oc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
Methyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yloxy)phenyl)acetate (450 mg, 0.81 mmol) was dissolved in ACN (15 mL) and NIS (200 mg, 0.88 mmol) was added. The resulting mixture was stirred at room temperature for 2 h and then the solvent was removed under reduced pressure. The residue was purified with column (silica gel, 10% EtOAc/Hexane) gave the product, methyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yloxy)phenyl)acetate (541 mg) as yellowish oil. HPLC-MS tR=2.96 min (UV254 nm); mass calculated for formula C27H41IN4O5Si2 684.2, observed LCMS m/z 685.2 (M+H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[N:7]=1.CO.C([O-])=O.[NH4+]>C1COCC1.C(Cl)Cl.[Pd]>[O:19]1[CH2:18][CH2:17][N:16]([C:4]2[C:5]3[N:6]([CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=3)[N:7]=[CH:2][CH:3]=2)[CH2:21][CH2:20]1
Reactant: CCOC(=O)c1cn2nc(Cl)cc(N3CCOCC3)c2n1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1cn2nccc(N3CCOCC3)c2n1

Procedure:
Compound 5b (8.6 g, 28 mmol) was suspended in THF (100 mL)/MeOH (50 mL). The reaction mixture was purged with argon, and 10% Pd/C (1.5 g, 1.4 mmol) was added followed by solid ammonium formate (8.7 g, 140 mmol). The reaction mixture was stirred under reflux for 1 h, during which time some of the ammonium formate sublimed onto the reflux condenser. The solid was rinsed back into the reaction flask with dry MeOH. The reaction mixture was filtered through a pad of diatomaceous earth. The filtrate was concentrated in vacuo to obtain a solid, which was dissolved in DCM (200 mL), and washed with water (100 mL) and brine (100 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give compound 5c as a white solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.34 (s, 1H), 8.04 (d, J=5.6 Hz, 1H), 6.06 (d, J=5.6 Hz, 1H), 4.43 (q, J=7.1 Hz, 2H), 3.98-4.07 (m, 4H), 3.88-3.96 (m, 4H), 1.42 (t, J=7.1 Hz, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:28][CH2:27][C:10]2([CH2:13][CH:12]([N:14]3[CH2:19][CH2:18][CH:17]([C:20](=[O:26])[NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:16][CH2:15]3)[CH2:11]2)[CH2:9]1)=O)(C)(C)C.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30]>C(Cl)Cl>[F:32][C:31]([F:34])([F:33])[C:29]([OH:35])=[O:30].[CH2:11]1[C:10]2([CH2:27][CH2:28][NH:8][CH2:9]2)[CH2:13][CH:12]1[N:14]1[CH2:15][CH2:16][CH:17]([C:20]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:26])[CH2:18][CH2:19]1
Reactant: CC(C)(C)NC(=O)C1CCN(C2CC3(CCN(C(=O)OC(C)(C)C)C3)C2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)C1CCN(C2CC3(CCNC3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl-2-[4-(tert-butylcarbamoyl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (0.627 g, 1.55 mmol) was dissolved in DCM (4 mL) and TFA (1 mL) was added. The reaction mixture was stirred at rt overnight under nitrogen, then the solvents were removed in vacuo, to give 1-(6-azaspiro[3.4]oct-2-yl)-N-tert-butylpiperidine-4-carboxamide trifluoroacetate (1:2) as an oil which was used directly without further purification. The residue was dissolved in DCM (8 mL) and NEt3 (0.056 g, 0.08 mL, 0.54 mmol) and ethyl chloroformate (0.024 mg, 0.02 mL, 0.22 mmol) were added and the reaction mixture was stirred at rt overnight under nitrogen. The solvents were removed in vacuo, and the residue was partitioned between DCM and sat. NaHCO3 sol., organic layer washed with sat. NaCl sol. and dried over MgSO4. The residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 10 g, 40-63 μm, 60 A, 12 mL per min, gradient 0% to 10% MeOH in DCM]) to give ethyl 2-[4-(tert-butylcarbamoyl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (0.027 g, 41%) as an off-white solid as a mixture of diastereomers.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:6][CH:5]=1.[C:17]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.C([BH3-])#N.[Na+].[OH-].[Na+]>ClCCl.CO.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:33][C:30]2[CH:29]=[CH:28][C:27]([C:24]3[CH:25]=[CH:26][C:21]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:22][CH:23]=3)=[CH:32][CH:31]=2)[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(=O)CC(C)C)cc1
Reactant: CC(C)(C)c1ccc(-c2ccc(N)cc2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccc(C(CC(C)C)Nc2ccc(-c3ccc(C(C)(C)C)cc3)cc2)cc1
Reaction time: 2 h
Yield: 83.6 %

Procedure:
To a solution of 4-(3-methyl-butyryl)-benzoic acid methyl ester (Preparation 4) (440 mg, 2 mmol) in dichloromethane (30 mL) is added 4′-tert-butyl-biphenyl-4-ylamine (Preparation 1) (450 mg, 2 mmol), and triethylamine (606 mg, 6 mmol). Titanium(IV) chloride in dichloromethane (1M, 1 mL) is added dropwise. The reaction is monitored by TLC. Once the starting material is consumed, the reaction is carefully quenched with sodium cyanoborohydride (377 mg, 6 mmol) in MeOH (5 mL) and stirred for 2 h. The reaction is adjusted to pH=13 with 5N NaOH, extracted with EtOAc, dried (Na2SO4), and concentrated under reduced pressure. The resulting residue is purified by silica gel chromatography, eluting with dichloromethane to afford 718 mg of the titled compound. 1H-NMR.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][CH:6]=2.[CH3:20][O:21][CH2:22][CH2:23]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.COCO>C1C=CC=CC=1.CCCCCC>[CH3:20][O:21][CH2:22][CH2:23][O:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][CH:6]=2
Reactant: CC(C)(C)OC(=O)Cc1ccc2ncc(O)cc2c1
Reactant: COCCO
Agent: CCCCP(CCCC)CCCC
Agent: COCO
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: c1ccccc1
Product: COCCOc1cnc2ccc(CC(=O)OC(C)(C)C)cc2c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of tert-butyl 2-(3-hydroxyquinolin-6-yl)acetate (0.1 g, 0.4 mmol) in benzene (5 mL) was added 2-methoxyethanol (0.09 ml, 1 mmol) and tri-n-butylphosphine (0.1 ml, 0.6 mmol). The resulting mixture was cooled to 0° C. followed by adding 1,1′-(azodicarbonyl)dipiperidine (0.1 g, 0.6 mmol). After 10 min, ice bath was removed; the reaction mixture was warmed up to rt. After 2 h, TLC showed there still existed 50% starting material. More methoxymethanol (2 eq, 0.06 mL) was added. The reaction mixture was continued to stir for 20 h. Hexane was added to the reaction mixture and dihydro-ADDP separated out was filtered off. The filtrate was concentrated. The crude product was purified using SiO2 chromatography (TELEDYNE ISCO REDISEP®, P/N 68-2203-027, 40 g SiO2, hexane:acetone=85%:15%, Flow=40 mL/min) to afford the desired product as colorless liquid. MS m/z: 318.4 (M+H). Calc'd. for C18H23NO4−317.38.
Reaction SMILES: [OH:1][CH:2]([C:18]1[CH:22]=[C:21]([Si:23]([CH3:26])([CH3:25])[CH3:24])[O:20][CH:19]=1)[CH2:3][CH2:4][CH2:5][CH:6]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)[CH3:7].[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([O:1][CH:2]([C:18]1[CH:22]=[C:21]([Si:23]([CH3:25])([CH3:24])[CH3:26])[O:20][CH:19]=1)[CH2:3][CH2:4][CH2:5][CH:6]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)[CH3:7])(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: CC(CCCC(O)c1coc([Si](C)(C)C)c1)c1ccc2ccccc2c1
Solvent: c1ccncc1
Product: CC(=O)OC(CCCC(C)c1ccc2ccccc2c1)c1coc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-[1-hydroxy-5-(2-napthyl)hexyl]-5-trimethylsilylfuran (120 mg, 0.3 mmol) and acetic anhydride (66 mg, 651 mmol) in pyridine (1.3 ml) was stirred at room temperature overnight. After removal of the solvent, the residue was purified by preparative TLC (20×20 cm, 500μ silica gel plate; developed with 30% ethyl ether/hexane) yielding the title compound as a yellow oil.