Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:49])[CH:5]=[C:6]([Cl:48])[C:7]=1[CH2:8][C@H:9]([O:20][C:21]([C:23]1[S:24][C:25]([CH2:28][NH:29][CH:30]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:31](=[O:41])[O:32][C@@H:33]2[CH:38]3[CH2:39][CH2:40][N:35]([CH2:36][CH2:37]3)[CH2:34]2)=[CH:26][CH:27]=1)=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.[CH:50](=O)[CH3:51].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C(F)(F)F>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:49])[CH:5]=[C:6]([Cl:48])[C:7]=1[CH2:8][C@H:9]([O:20][C:21]([C:23]1[S:24][C:25]([CH2:28][N:29]([CH2:50][CH3:51])[CH:30]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:31](=[O:41])[O:32][C@@H:33]2[CH:38]3[CH2:37][CH2:36][N:35]([CH2:40][CH2:39]3)[CH2:34]2)=[CH:26][CH:27]=1)=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: CC=O
Reactant: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(CNC(C(=O)O[C@H]3CN4CCC3CC4)c3ccccc3)s2)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: OCC(F)(F)F
Solvent: CC(=O)O
Product: CCN(Cc1ccc(C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC)c(OC)c2)s1)C(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 40 °C
Yield: 25.4 %

Procedure:
A suspension of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]5-[[[2-oxo-1-phenyl-2-[(3R)-quinuclidin-3-yl]oxy-ethyl]amino]methyl]thiophene-2-carboxylate (Example 42, 100 mg, 0.12 mmol) in trifluoroethanol (0.5 mL) was heated at 40 C for 5 min. Acetaldehyde (11 μL, 0.19 mmol) was added followed by acetic acid (7 μL, 0.12 mmol) and the reaction mixture was heated at 40° C. for 18 h. Sodium triacetoxyborohydride (52 mg, 0.25 mmol) was added and the mixture was heated at 40° C. for 2 h. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate (1 mL) and water (1 mL). 0.2N aqueous HCl was added to adjust pH=1. The acidic aqueous phase was washed with ethyl acetate (3×1 mL), sodium chloride (1 g) was added to the aqueous phase that was extracted with chloroform (3×1 mL), the combined chloroform extracts were filtered through a phase separator and the solvent was removed in vacuo. The combined ethyl acetate washes were extracted with 0.2N HCl (1 mL), water (1 mL). The aqueous phases were combined, saturated with solid sodium chloride and extracted with chloroform (3×1 mL). The crude product from both extractions was combined and purification by preparative HPLC gave the title compound as an off-white solid (23 mg, 24%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:12]([CH2:23][CH3:24])=[N:11][CH:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[C:3]([C:9]2[CH:10]=[N:11][C:12]([CH2:23][CH3:24])=[C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:14]=2)=[CH:4][C:5]([NH:25][C@H:26]2[CH2:31][CH2:30][C@H:29]([NH2:32])[CH2:28][CH2:27]2)=[N:6][CH:7]=1
Reactant: CCc1ncc(-c2cc(F)ncc2Cl)nc1NCC1CCOCC1
Reactant: NC1CCC(N)CC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCc1ncc(-c2cc(N[C@H]3CC[C@H](N)CC3)ncc2Cl)nc1NCC1CCOCC1
Temperature: 100 °C
Reaction time: 17 h

Procedure:
6-(5-chloro-2-fluoropyridin-4-yl)-3-ethyl-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazine-2-amine (0.0053 g, 0.015 mmol) was dissolved in DMSO (1 ml). This was treated with 1,4-diaminocyclohexane (0.017 g, 0.151 mmol). The reaction mixture was then heated at 100° C. for 4 hr. Additional 1,4-diaminocyclohexane (0.017 g, 0.151 mmol) and triethylamine (0.0084 ml, 0.012 g, 0.060 mmol) were added. Heating at 100° C. was continued for 17 hr. The reaction mixture was purified using prep HPLC. The material was purified by preparative reverse-phase HPLC to give 0.0040 g of trans-N1-(5-chloro-4-(5-ethyl-6-((tetrahydro-2H-pyran-4-yl)methyl)aminopyrazin-2-yl)pyridin-2-yl)cyclohexane-1,4-diamine as the TFA salt. LCMS (m/z): 445.2 (MH+), retention time=0.54 min.
Reaction SMILES: C([S:4][CH2:5][CH:6]([S:21][CH3:22])[C:7]([N:9]1[CH2:16][C:15]([O:19][CH3:20])([O:17][CH3:18])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=O)C.N>>[SH:4][CH2:5][CH:6]([S:21][CH3:22])[C:7]([N:9]1[CH2:16][C:15]([O:19][CH3:20])([O:17][CH3:18])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8]
Reactant: COC1(OC)C[C@@H](C(=O)O)N(C(=O)C(CSC(C)=O)SC)C1
Agent: N
Product: COC1(OC)C[C@@H](C(=O)O)N(C(=O)C(CS)SC)C1

Procedure:
The product from part (a) is hydrolyzed with concentrated ammonia according to the procedure of Example 4 to yield 1-(3-mercapto-2-methylthio-1-oxopropyl)-4,4-dimethoxy-L-proline.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:58])([F:57])[C:10]1[CH:11]=[C:12]([C:20]([CH3:56])([CH3:55])[C:21]([N:23]([CH3:54])[C:24]2[C:25]([C:46]3[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:47]=3[CH3:53])=[CH:26][C:27]([C:30]#[C:31][CH2:32][C@@H:33]([NH:38]C(OC(C)(C)C)=O)[C:34]([O:36][CH3:37])=[O:35])=[N:28][CH:29]=2)=[O:22])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1>ClCCl.C([O-])(O)=O.[Na+]>[NH2:38][C@H:33]([CH2:32][C:31]#[C:30][C:27]1[CH:26]=[C:25]([C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:47]=2[CH3:53])[C:24]([N:23]([C:21](=[O:22])[C:20]([C:12]2[CH:11]=[C:10]([C:9]([F:57])([F:58])[F:8])[CH:15]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:13]=2)([CH3:55])[CH3:56])[CH3:54])=[CH:29][N:28]=1)[C:34]([O:36][CH3:37])=[O:35]
Reactant: COC(=O)[C@@H](CC#Cc1cc(-c2ccc(F)cc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H](N)CC#Cc1cc(-c2ccc(F)cc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
Trifluoroacetic acid (15 ml) was added dropwise to an ice-cooled solution of methyl (2R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-pentynoate (Intermediate 12, 2.4 g, 3.32 mmol) in anhydrous Dichloromethane (45 ml) and the resulting reaction mixture was stirred at room temperature for 1 h. Volatiles were evaporated. The reaction crude was taken-up in saturated NaHCO3 aqueous solution [until pH=7] (30 ml) and extracted with DCM (2×50 ml). The organic layers were collected, dried over sodium sulphate, filtered and evaporated to obtain the title compound (1.85 g, 2.97 mmol, 89% yield) as a brown solid. UPLC: Rt 0.78 min, m/z 624 [M+H+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:31]C(=O)OC(C)(C)C)[CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]3[N:23]([CH2:24][CH2:25][F:26])[C:22]4[CH:27]=[CH:28][CH:29]=[CH:30][C:21]=4[N:20]=3)[CH2:14]2)=[O:12])=[CH:4][CH:3]=1.[NH2:39][C:40]1[N:45]=[CH:44][C:43](B(O)O)=[CH:42][N:41]=1.C(O)(C(F)(F)F)=O.N[C@H](CC1C=CC(C2C=CC=CC=2)=CC=1)CC(N1CCC[C@@H](C2N(CCCOC)C3C=CC=CC=3N=2)C1)=O>>[NH2:31][C@H:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([C:43]2[CH:42]=[N:41][C:40]([NH2:39])=[N:45][CH:44]=2)=[CH:7][CH:6]=1)[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]2[N:23]([CH2:24][CH2:25][F:26])[C:22]3[CH:27]=[CH:28][CH:29]=[CH:30][C:21]=3[N:20]=2)[CH2:14]1)=[O:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCC[C@@H](c2nc3ccccc3n2CCF)C1)Cc1ccc(Br)cc1
Reactant: Nc1ncc(B(O)O)cn1
Agent: COCCCn1c([C@@H]2CCCN(C(=O)C[C@H](N)Cc3ccc(-c4ccccc4)cc3)C2)nc2ccccc21
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(-c2ccc(C[C@@H](N)CC(=O)N3CCC[C@@H](c4nc5ccccc5n4CCF)C3)cc2)cn1
Yield: 14.4 %

Procedure:
Suzuki coupling of 145A with 2-aminopyrimidin-5-ylboronic acid (145E) was carried out analogously to the synthesis of Compound 613 (Example 6, Step B). The crude Boc-protected intermediate was de-protected with TFA using procedure similar to that for the synthesis of Compound 72 from Compound 6B (Example 6, Step C). The crude product was purified by preparative HPLC using 15% CH3CN/water as mobile phase. Compound 509 was obtained in 14.4% yield over two steps (17.8 mg), MS: MH+=502.4.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=O.[NH:8]1[CH2:13][CH2:12][C:11]2([C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C@@H:16]([NH:23][C:24](=[O:26])[CH3:25])[CH2:15][CH2:14]2)[CH2:10][CH2:9]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>ClCCl.C(O)(=O)C>[CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][N:8]1[CH2:13][CH2:12][C:11]2([C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C@@H:16]([NH:23][C:24](=[O:26])[CH3:25])[CH2:15][CH2:14]2)[CH2:10][CH2:9]1
Reactant: CC(=O)N[C@H]1CCC2(CCNCC2)c2ccccc21
Reactant: CC(C)(C)CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)N[C@H]1CCC2(CCN(CCC(C)(C)C)CC2)c2ccccc21
Reaction time: 5 h

Procedure:
A solution of 3,3-dimethylbutyraldehyde (13 mg, 0.13 mmol) and the spiro-piperidine (B5) (25 mg, 0.10 mmol) in dry dichloromethane (2 ml) was stirred at room temperature for 30 min, cooled with ice-bath, and treated with sodium triacetoxyborohydride (44 mg, 0.2 mml), followed by acetic acid (1 drop) and methanol (1 ml). The reaction mixture was stirred for another 5 hours and concentrated under a stream of nitrogen. The residue was dissolved in methanol (1 ml) and purified by reverse phase HPLC to give the title compound no. 17 as a TFA salt. LC-MS: m/e=343.30 (M+H). Rt=1.63 min. 1H-NMR (500 MHz, DMSO-d6): 9.28 (br.s, 1H), 8.18 (d, 1H), 7.35 (d, 1H), 7.30 (t, 1H), 7.19 (t, 1H), 7.16 (d, 1H), 4.92 (m, 1H), 3.45 (m, 2H), 3.14 (m, 4H), 2.19 (m, 2H), 2.05 (m, 1H), 1.87 (s, 3H), 1.82 (m, 2H), 1.73 (d, 1H), 1.60 (m, 3H), 0.93 (m, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([NH:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[CH:3]=1.[C:15]([C:18]1[C:19](=[O:29])[O:20][C:21]([OH:28])=[C:22]([C:25](=O)[CH3:26])[C:23]=1[OH:24])(=[O:17])[CH3:16]>CO>[C:15]([C:18]1[C:19](=[O:29])[O:20][C:21](=[O:28])[C:22](=[C:25]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([NH:9][C:10](=[O:14])[CH:11]([CH3:12])[CH3:13])[CH:3]=2)[CH3:26])[C:23]=1[OH:24])(=[O:17])[CH3:16]
Reactant: CC(C)C(=O)Nc1cc(N)ccc1O
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Solvent: CO
Product: CC(=O)C1=C(O)C(=C(C)Nc2ccc(O)c(NC(=O)C(C)C)c2)C(=O)OC1=O

Procedure:
This phenol (0.86 g., 0.0045 mol) is refluxed with 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one (0.96 g.) in 50 ml. of methanol for 10 hours. The reaction mixture is filtered and the solid is recrystallized from ethanol to furnish 5-acetyl-4-hydroxy-3-[1-(3-isobutyramido-4-hydroxyphenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 208°-209° C. (dec.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.C([O:11][CH:12]([CH2:17][CH2:18][N:19]=[N+:20]=[N-:21])[C:13]([O:15][CH3:16])=[O:14])(=O)C.[Cl-].[NH4+]>CO>[N:19]([CH2:18][CH2:17][CH:12]([OH:11])[C:13]([O:15][CH3:16])=[O:14])=[N+:20]=[N-:21]
Reactant: COC(=O)C(CCN=[N+]=[N-])OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)C(O)CCN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.2 %

Procedure:
2.53 g of potassium carbonate and 1 ml of water were added to a methanol (15 ml) solution of 2.47 g of methyl 2-(acetyloxy)-4-azidobutanoate, and stirred at room temperature for 30 minutes. Aqueous saturated ammonium chloride solution was added to the reaction liquid, and extracted with ethyl acetate. The organic layer was washed with saturated saline water and dried. The solvent was evaporated away under reduced pressure to obtain 591 mg of methyl 4-azido-2-hydroxybutanoate as an orange oil.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:23]([O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:40][CH2:41][CH3:42])[C:34]=1[C:35]1[CH:36]=[N:37][NH:38][CH:39]=1)[C:29]([OH:31])=O)[CH3:24].Cl.[O:44]=[C:45]1[O:49][N:48]=[C:47]([C:50]2[CH:51]=[C:52]3[C:62](=[CH:63][CH:64]=2)[O:61][C:55]2([CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)[CH2:54][C:53]3=[O:65])[NH:46]1>O.CN(C=O)C.CCN(CC)CC>[CH2:41]([O:40][C:33]1[CH:32]=[C:28]([C:29]([N:58]2[CH2:59][CH2:60][C:55]3([CH2:54][C:53](=[O:65])[C:52]4[C:62](=[CH:63][CH:64]=[C:50]([C:47]5[NH:46][C:45](=[O:44])[O:49][N:48]=5)[CH:51]=4)[O:61]3)[CH2:56][CH2:57]2)=[O:31])[CH:27]=[C:26]([O:25][CH2:23][CH3:24])[C:34]=1[C:35]1[CH:36]=[N:37][NH:38][CH:39]=1)[CH3:42]
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3noc(=O)[nH]3)cc21
Reactant: CCOc1cc(C(=O)O)cc(OCC)c1-c1cn[nH]c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4noc(=O)[nH]4)ccc2O3)cc(OCC)c1-c1cn[nH]c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Et3N (83 μL), HOBT (46 mg) and WSC hydrochloride (58 mg) were added to a DMF (4 mL) solution of 3,5-diethoxy-4-(1H-pyrazol-4-yl)benzoic acid (101 mg) and 6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (70 mg), and stirred overnight at room temperature. Water was added to the reaction liquid, the formed solid was taken out through filtration, and the solid was washed with water and ether. The solid was dried under reduced pressure to obtain the title compound. 1H-NMR (400 MHz, DMSO-d6) δ: 12.96 (1H, s), 8.21 (1H, d, J=4.0 Hz), 8.06 (2H, s), 8.00 (11, dd, J=8.0, 4.0 Hz), 7.30 (1H, d, J=8.0 Hz), 6.68 (2H, s), 4.32-4.18 (1H, m), 4.08 (4H, q, J=8.0 Hz), 3.64-3.20 (3H, m), 2.97 (2H, s), 2.10-1.75 (4H, m), 1.37 (6H, t, J=8.0 Hz). MS [M+H]+=560.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[CH:3]=1.[H-].[Na+].[C:21](=[O:28])([O:25][CH2:26][CH3:27])OCC>O>[O:18]=[C:4]1[CH:3]=[C:2]([CH:1]([C:21]([O:25][CH2:26][CH3:27])=[O:28])[C:21]([O:25][CH2:26][CH3:27])=[O:28])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)OCC
Reactant: Cc1cc(=O)n(-c2ccccc2)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(C(=O)OCC)c1cc(=O)n(-c2ccccc2)c2ccccc12

Procedure:
A mixture of 1,2-dihydro-4-methyl-2-oxo-1-phenylquinoline (4.7 g.), sodium hydride (4.8 g., 60% w/w dispersion in oil, washed as in Example 1) and diethyl carbonate (50 ml.) was stirred under reflux for 2 hours. Any excess of sodium hydride was then destroyed by addition of methanol to the cooled suspension, and the mixture was then poured into ether (1 l.). The yellow precipitate was collected by filtration, and washed with ether (200 ml.). It was suspended in ethanol (50 ml.), concentrated hydrochloric acid was added to give a pH of 3, and the resultant solution was poured into water (200 ml.). The precipitate was extracted into ether, and the combined extracts were washed with water, dried over magnesium sulphate, and evaporated in vacuo. A sample of the residual solid was recrystallised from a mixture of benzene and cyclohexane to give diethyl 1,2-dihydro-2-oxo-1-phenylquinol-4-ylmalonate, m.p. 101°-103° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)[OH:7].Cl[CH2:13][CH:14]=[C:15]([CH3:35])[CH2:16][CH2:17][CH2:18][C:19]([Cl:34])([CH3:33])[CH2:20][CH2:21][CH2:22][C:23]([Cl:32])([CH3:31])[CH2:24][CH2:25][CH2:26][C:27]([Cl:30])([CH3:29])[CH3:28].[Cl-].[NH4+]>O1CCOCC1.[Cl-].[Zn+2].[Cl-]>[CH3:35][C:15]1([CH2:16][CH2:17][CH2:18][C:19]([Cl:34])([CH3:33])[CH2:20][CH2:21][CH2:22][C:23]([Cl:32])([CH3:31])[CH2:24][CH2:25][CH2:26][C:27]([Cl:30])([CH3:29])[CH3:28])[CH2:14][CH2:13][C:8]2[C:6](=[C:5]([CH3:9])[C:4]([CH3:10])=[C:3]([OH:11])[C:2]=2[CH3:1])[O:7]1
Reactant: CC(=CCCl)CCCC(C)(Cl)CCCC(C)(Cl)CCCC(C)(C)Cl
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn+2]
Solvent: C1COCCO1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCCC(C)(Cl)CCCC(C)(Cl)CCCC(C)(C)Cl)O2
Reaction time: 0.5 h
Yield: 43.5 %

Procedure:
Molten zinc chloride (0.22 g), trimethylhydroquinone (2.47 g) and anhydrous dioxane (10 cc) are introduced into a 250 cc reactor. The mixture is heated to 40°-45° C. and a solution of 1,7,11,15-tetrachloro-3,7,11,15-tetramethyl-hexadec-2-ene (6.8 g) in dioxane (7 cc) is then added over the course of 20 minutes. Stirring is continued for 1 hour 30 minutes. The reaction mixture is poured into an aqueous solution (50 cc) of ammonium chloride (100 g/liter). The batch is extracted with ethyl acetate (twice 50 cc) and the organic phases are then dried over magnesium sulphate. After filtration and evaporation of the solvent, 2,5,7,8-tetramethyl-2-(4',8',12'-trichloro-4',8',12'-trimethyltridecyl)-chroman-6-ol is obtained in a yield of 43.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Mg]Cl)[CH:5]=[CH:6][CH:7]=1.CON(C)[C:13]([C@@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1)=[O:14]>C1COCC1>[C:24]([O:23][C:21]([N:17]1[CH2:18][CH2:19][CH2:20][C@@H:15]([C:13](=[O:14])[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:16]1)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: Cl[Mg]c1cccc(Cl)c1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 132.6 %

Procedure:
At −20° C., 3-chlorophenyl magnesium chloride (11 mL, 5.5 mmol, 0.5M THF solution) was added dropwise to a solution of (R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate (500 mg, 1.84 mmol) in THF (5 mL). The solution was stirred for 2 h and allowed to warm to rt. The reaction was quenched with satd ammonium chloride solution. The aqueous layer was extracted with ether (3×). The combined organic layers were washed with brine, dried over MgSO4 and filtered. Evaporation of solvent provided (3R)-1-(tert-butoxycarbonyl)-3-(3-chlorobenzoyl)piperidine (0.79 g) as an oil that was used without purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([CH3:18])([C:14]([O:16]C)=[O:15])[C:10]([O:12]C)=[O:11])=[CH:4][CH:3]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([CH3:18])([C:14]([OH:16])=[O:15])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(Cc1ccc(Cl)nc1)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(Cc1ccc(Cl)nc1)(C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a stirred solution of dimethyl 2-[(6-chloropyridin-3-yl)methyl]-2-methylmalonate (10.85 g, 40 mmol) in THF (80 mL) was added a solution of lithium hydroxide monohydrate (5.7 g, 0.136 mol) in water (43 mL). The resulting mixture was stirred overnight at room temperature and then poured into water (300 mL). The pH was adjusted to less than 2 by the addition of concentrated HCl. The resulting mixture was extracted with ether (3×100 mL) and the ether extracts were combined, washed with brine (100 mL) and dried over anhydrous MgSO4. After a filtration, the solvent was evaporated to give 9.26 g of the product as a white solid in 95% yield: m.p. 168° C. (decomp.).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6](B(O)O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:21][C:22]([CH3:32])=[C:23]([CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[N:24]=2)=[CH:16][CH:15]=1>>[CH3:32][C:22]1[O:21][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)=[CH:15][CH:16]=2)=[N:24][C:23]=1[CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCC1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Product: Cc1oc(-c2ccc(-c3ccc4[nH]ccc4c3)cc2)nc1CCN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Example 45 starting from 5-Indole boronic acid and 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-1-yl-ethyl)-oxazole. MS (m/e): 372.2 (M+1)
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH:7]([N:10]2[C:19](=[O:20])[CH2:18][C:17]3[C:12](=[CH:13][C:14]([O:23][CH:24]([CH3:26])[CH3:25])=[C:15]([O:21][CH3:22])[CH:16]=3)[CH:11]2[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:34][Mg]Br>C1COCC1>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH:11]2[C:12]3[C:17](=[CH:16][C:15]([O:21][CH3:22])=[C:14]([O:23][CH:24]([CH3:26])[CH3:25])[CH:13]=3)[CH2:18][C:19](=[O:20])[N:10]2[CH:7]2[CH2:6][CH2:5][CH:4]([C:1]([OH:3])([CH3:34])[CH3:2])[CH2:9][CH2:8]2)=[CH:32][CH:31]=1
Reactant: C[Mg]Br
Reactant: COc1cc2c(cc1OC(C)C)C(c1ccc(Cl)cc1)N(C1CCC(C(C)=O)CC1)C(=O)C2
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC(C)C)C(c1ccc(Cl)cc1)N(C1CCC(C(C)(C)O)CC1)C(=O)C2
Reaction time: 2 h
Yield: 16.6 %

Procedure:
To the stirred solution of Example 15 (100 mg, 0.211 mmol) in THF (1.05 ml) was added methylmagnesium bromide (3M in diethyl ether) (0.126 ml, 0.329 mmol) during 2 min at −15° C. Stirring was continued for 2 h at RT and then quenched with 1M NH4Cl. The mixture was extracted with EtOAc (2×). The organic phases were washed with brine and dried over Na2SO4, filtered and evaporated to dryness. The resulting crude material was purified by reverse phase prep-HPLC (Waters system) to yield the title compound as a beige foam (17 mg, 0.035 mmol, 17%). HPLC: BtRet=5.71; LC-MS: m/z 486.3 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][C:17]([NH:19][C:20]2[C:25]([O:26]C(=O)CC3C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=3)=[C:24]([Br:45])[CH:23]=[C:22]([Cl:46])[CH:21]=2)=[O:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl>CO>[Br:45][C:24]1[CH:23]=[C:22]([Cl:46])[CH:21]=[C:20]([NH:19][C:17](=[O:18])[CH2:16][C:7]2[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]([OH:11])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=2)[C:25]=1[OH:26]
Reactant: CC(C)(C)c1cc(CC(=O)Nc2cc(Cl)cc(Br)c2OC(=O)Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)c1cc(CC(=O)Nc2cc(Cl)cc(Br)c2O)cc(C(C)(C)C)c1O
Yield: 88.9 %

Procedure:
A solution of N,O-Di-(3,5-di-t-butyl-4-hydroxy-phenylacetyl)-6-amino-2-bromo-4-chloro-phenol (58.1 g, 89.8 mmol) in methanol (400 ml) and potassium carbonate (24.78 g, 180 mmol) was stirred at room temperature for 10 minutes. The methanol was removed in-vacuo, the residue treated with 2 N HCl (180 ml, 360 mmol), and extracted with ethyl acetate (300 ml). The organics were dried (Na2SO4), evaporated in-vacuo, and the residue suspended in petroleum ether. The precipitate was collected to give 37.44 g (88.9%) of the title compound which was suitable for the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[OH:28].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.[Cu]I>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[O:28][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9]
Reactant: O=C(c1ccncc1Br)N1CCCc2ccccc21
Reactant: Oc1cc(Cl)ccc1Cl
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(c1ccncc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Temperature: 180 °C
Yield: 9.6 %

Procedure:
To a solution of (3-bromo-pyridin-4-yl)-(3,4-dihydro-2H-quinolin-1-yl)-methanone (41.2 mg, 0.13 mmol, 1.0 equiv) and 2,5-dichloro-phenol (21.2 mg, 0.13 mmol, 1.0 equiv; [CAS RN 583-78-8]) in DMAc (1 mL) was added potassium carbonate (35.9 mg, 0.26 mmol, 2.0 equiv; [CAS RN 584-08-7]) and copper(I) iodide (5.0 mg, 0.026 mmol, 0.2 equiv; [CAS RN 7681-65-4]). The reaction mixture was heated by microwave irradiation to 180° C. for 8 h. Purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 5 mg (10%) of the title compound. MS (ISP): 399.1 [M+H]+.