Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=3[O:30][CH2:31][CH3:32])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:40](Cl)([Cl:42])=[O:41]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:40]([Cl:42])=[O:41])[C:10]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][C:21]=3[O:30][CH2:31][CH3:32])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To a solution of 4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-1H-imidazole (46 g, 95.97 mmol, example 1) and triethylamine (66.9 mL, 479.9 mmol) in methylene chloride (2 L) cooled to 0° C. was added phosgene (124.3 mL, 239.9 mmol, ˜20% solution in toluene) dropwise over a period of 30 min. The reaction mixture was stirred at room temperature for 1 h. Nitrogen gas was bubbled through the reaction mixture to remove excess phosgene. The reaction mixture was concentrated to dryness, and the residue was dried in vacuo for 1 h to give 4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (51 g, 98% yield) as off-white solids. The product was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[C:15]2[O:14][CH2:13][CH2:12][C:11]=2[C:10]([OH:16])=[CH:9][CH:8]=1)[CH3:2].Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:26][C:27]=1[CH3:28].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[C:15]2[O:14][CH2:13][CH2:12][C:11]=2[C:10]([O:16][CH2:22][C:23]2[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:26][C:27]=2[CH3:28])=[CH:9][CH:8]=1)[CH3:2]
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: CCOC(=O)C(Cc1ccc(O)c2c1OCC2)OCC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccccc3)oc2C)c2c1OCC2)OCC

Procedure:
In analogy to the procedure described in example 120 f], [rac]-2-ethoxy-3-(4-hydroxy-2,3-dihydro-benzofuran-7-yl)-propionic acid ethyl ester was reacted with 4-chloromethyl-5-methyl-2-phenyl-oxazole in the presence of potassium carbonate and potassium iodide to yield [rac]-2-ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-2,3-dihydro-benzofuran-7-yl]-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 120 f] to yield [rac]-2-ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-2,3-dihydro-benzofuran-7-yl]-propionic acid as white solid.
Reaction SMILES: [C:1]([C:4]1([CH3:26])[C:9]([NH2:10])=[CH:8][C:7]([C:11](N2C3C(=CC=CC=3)C(C)CC2(C)C)=[O:12])=[CH:6][CH2:5]1)(=[O:3])[CH3:2].[O:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[C:32](Cl)=[O:33].[CH:35]([N:38](CC)[CH:39]([CH3:41])[CH3:40])([CH3:37])[CH3:36]>O1CCCC1>[C:1]([C:4]1([CH3:26])[C:9]([NH:10][C:32]([C:28]2[O:27][CH:31]=[CH:30][CH:29]=2)=[O:33])=[CH:8][CH:7]([C:11]([C:5]2[C:35]([CH3:36])([CH3:37])[NH:38][C:39]3[C:40]([C:6]=2[CH3:7])=[CH:4][CH:1]=[CH:2][CH:41]=3)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(=O)C1(C)CC=C(C(=O)N2c3ccccc3C(C)CC2(C)C)C=C1N
Reactant: O=C(Cl)c1ccco1
Solvent: C1CCOC1
Product: CC(=O)C1(C)CCC(C(=O)C2=C(C)c3ccccc3NC2(C)C)C=C1NC(=O)c1ccco1

Procedure:
Acylation of 1-acetyl-6-amino-4-toloyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 2-furoyl chloride (8.1 mg) and N,N-diisopropylethylamine (20 μl) in tetrahydrofuran (1 ml) was performed according to the method described in example 6.
Reaction SMILES: [NH:1]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C@H:2]([C:4]([NH:6][C@H:7]([C:9]([OH:11])=O)[CH3:8])=[O:5])[CH3:3].[CH2:22]([O:29][CH2:30]C1C=CC=CC=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Na].C(Cl)(Cl)Cl.C[OH:43]>C(O)C1C=CC=CC=1>[NH:1]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C@H:2]([C:4]([NH:6][CH:7]([C:9]([C:30]([O:29][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:43])=[O:11])[CH3:8])=[O:5])[CH3:3]
Reactant: c1ccc(COCc2ccccc2)cc1
Reactant: CO
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(=O)O
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: OCc1ccccc1
Product: CC(NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(=O)C(=O)OCc1ccccc1
Yield: 36 %

Procedure:
This compound was prepared from Z-Ala-Ala-OH in 36% yield by the procedure described in Example PKC1, except that benzyl oxalyl chloride was used in the Dakin-West reaction and sodium benzyloxide in benzyl alcohol was used for enol ester hydrolysis; single spot on tlc, Rf2 =0.55 (CHCl3 :MeOH=9:1); MS, m/e=413 (M+ +1). Anal. Calcd. for C22H24O6N2 : C, 64.06; H, 5.87; N, 6.79. Found: C, 63.79; H, 5.95; N, 6.72.
Reaction SMILES: Cl.[CH:2]1([N:6]([C@@H:10]2[CH2:15][C:14]3[C:16]([O:21]C)=[CH:17][CH:18]=[C:19]([F:20])[C:13]=3[O:12][CH2:11]2)[CH:7]([CH3:9])[CH3:8])[CH2:5][CH2:4][CH2:3]1.B(Br)(Br)Br.C(Cl)(Cl)Cl>C(Cl)Cl>[CH:2]1([N:6]([C@@H:10]2[CH2:15][C:14]3[C:16]([OH:21])=[CH:17][CH:18]=[C:19]([F:20])[C:13]=3[O:12][CH2:11]2)[CH:7]([CH3:9])[CH3:8])[CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(F)c2c1C[C@@H](N(C(C)C)C1CCC1)CO2
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)N(C1CCC1)[C@H]1COc2c(F)ccc(O)c2C1
Temperature: -40 °C
Yield: 97.9 %

Procedure:
(R)-3-(N-Cyclobutyl-N-isopropylamino)-8-fluoro-5-methoxy-3,4-dihydro-2H-1-benzopyran hydrochloride (1.76 g, 5.34 mmol) was dissolved in anhydrous CH2Cl2 (45 mL) and cooled to -40° C. To the solution was BBr3 (1.3 mL, 13.4 mmol), dissolved in anhydrous CH2Cl2 (7 mL), added dropwise. The cooling-bath was removed and after 2 h at room temperature the reaction was complete. The reaction was poured out onto an ice/2M NH3 solution and the CH2Cl2 portion was separated, the aqueous layer re-extracted, twice, with CH2Cl2. The combined CH2Cl2 portions were dried (MgSO4), filtered, and the solvent removed in vacuo to give the crude residue. Chromatography on silica (eluent: 30% ethyl acetate/hexane) gave 1.46 g (98% yield) of the title compound as a gum [α]21D =-95.7° (C=0.1; CHCl3) GC-MS (70 eV) M=279 (0.7%). The hydrochloride salt was made by dissolving the pure base in ether and dropping an excess of an ethereal HCl solution. The salt was washed with diethyl ether to give a white solid Mp: 120° C. sinters.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=1.I[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O.CN(C)P(N(C)C)(N(C)C)=O>[CH3:9][O:10][C:11](=[O:21])[CH:12]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=1)[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: ICC1CCCC1
Reactant: COC(=O)Cc1ccc(F)c(F)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C(CC1CCCC1)c1ccc(F)c(F)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 103 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (23.0 mL of a 0.31M stock solution, 7.13 mmol) cooled to −78° C. was treated with (3,4-difluoro-phenyl)-acetic acid methyl ester (1.20 g, 6.48 mmol) in tetrahydrofuran/hexamethylphosphoramide (16.1 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (1.50 g, 7.13 mmol) in hexamethylphosphoramide (1 mL). The reaction mixture was stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 16 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (20 mL). This mixture was poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-difluoro-phenyl)-propionic acid methyl ester (1.79 g, quant.) as a clear oil: EI-HRMS m/e calcd for C15H18F2O2 (M+) 268.1275, found 268.1278.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:13]=[CH:14][C:15](=[O:20])[N:16]([CH2:18][CH3:19])[CH:17]=2)=[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.[C:21](O)(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[CH2:18]([N:16]1[CH:17]=[C:12]([C:4]2[S:3][C:2]([NH:1][C:21]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[O:28])=[N:6][C:5]=2[C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[CH:13]=[CH:14][C:15]1=[O:20])[CH3:19]
Reactant: CCn1cc(-c2sc(N)nc2-c2ccco2)ccc1=O
Reactant: O=C(O)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCn1cc(-c2sc(NC(=O)c3ccncc3)nc2-c2ccco2)ccc1=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 25.2 %

Procedure:
2-Amino-5-(1-ethyl-2-oxo-1,2-dihydropyridin-5-yl)-4-(2-furyl)thiazole (287 mg, 1.00 mmol) obtained in Step 1 was dissolved in DMF (4 mL), and isonicotinic acid (246 mg, 2.00 mmol), PyBOP (1.14 g, 2.20 mmol) and triethylamine (0.613 mL, 4.40 mmol) were added thereto, followed by stirring at 80° C. for 1 hour. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=17:1), followed by reslurrying with a mixed solvent of methanol and diethyl ether to afford the entitled Compound 127 (99.0 mg, 25%) as a pale brown solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][C:25]=2[CH3:26])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)[CH3:5].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[C:48]([C:50]1[CH:58]=[C:57]([CH3:59])[C:53]([C:54](O)=[O:55])=[C:52]([CH3:60])[CH:51]=1)#[N:49].CCN(C(C)C)C(C)C>CN(C=O)C>[C:48]([C:50]1[CH:58]=[C:57]([CH3:59])[C:53]([C:54]([NH:1][CH2:2][CH2:3][C@H:4]([N:6]2[CH2:7][CH2:8][CH:9]([N:12]([CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][C:25]=3[CH3:26])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:11]2)[CH3:5])=[O:55])=[C:52]([CH3:60])[CH:51]=1)#[N:49]
Reactant: Cc1cc(C#N)cc(C)c1C(=O)O
Reactant: Cc1ccncc1CN(c1ccccc1)C1CCN([C@H](C)CCN)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccncc1CN(c1ccccc1)C1CCN([C@H](C)CCNC(=O)c2c(C)cc(C#N)cc2C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.9 %

Procedure:
[1-((R)-3-Amino-1-methyl-propyl)-piperidin-4-yl]-(4-methyl-pyridin-3-ylmethyl)-phenyl-amine (200.0 mg, 0.57 mmol), EDCI (120.0 mg, 0.62 mmol) and HOBT (84.3 mg, 0.62 mmol) were combined in DMF (25 mL) to give a pale yellow solution. To this solution was added 4-cyano-2,6-dimethyl-benzoic acid (109.3 mg, 0.62 mmol) followed by DIPEA (119.0 μL, 0.68 mmol) and the resulting mixture was stirred at room temperature for 16 h. Standard workup according to General Procedure C gave the crude product as a tan oil. Purification by column chromatography on silica gel (97:2:1, CH2Cl2/MeOH/NH4OH) afforded 4-cyano-2,6-dimethyl-N-((R)-3-{4-[(4-methyl-pyridin-3-ylmethyl)-phenyl-amino]-piperidin-1-yl}-butyl)-benzamide as an off-white foam (209.0 mg, 72%). 1H NMR (CDCl3) δ 1.02 (d, 3H, J=6 Hz), 1.04 (m, 1H), 1.30 (m, 1H), 1.59 (m, 1H), 1.64 (s, 2H), 1.76 (m, 1H), 1.86 (m, 2H), 2.21 (t, 1H, J=11 Hz), 2.32 (s, 6H), 2.55 (t, 1H, J=11 Hz), 2.78 (m, 3H), 2.87 (s, 2H), 2.95 (s, 3H), 3.35 (m, 1H), 3.64 (m, 1H), 3.78 (sext, 1H, J=6 Hz), 4.07 (s, 2H), 6.59 (d, 2H, J=9 Hz), 6.73 (t, 1H, J=8 Hz), 7.14 (m, 3H), 7.50 (m, 1H), 8.01 (s, 1H), 8.28 (s, 1H), 8.35 (d, 1H, J=5 Hz).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH:4]=[O:5].[C-:11]#[N:12].[K+].OS([O-])=O.[Na+]>C(OCC)(=O)C.O>[F:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH:4]([OH:5])[C:11]#[N:12]
Reactant: O=Cc1cc(Cl)ccc1F
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: N#CC(O)c1cc(Cl)ccc1F
Reaction time: 8 h
Yield: 98.3 %

Procedure:
To 2-fluoro-5-chloro-benzaldehyde (12.7 g, 17 mmol) in ethyl acetate (50 mL) was added a solution of KCN (3.3 g) and NaHSO3 (5.3 g) dissolved in H2O (25 mL). It was left stirring overnight before extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried and concentrated. The crude product was purified by silica gel chromatography to give 121A (3.1 g, 99% yield) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[S:20]([O:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:22])(=[O:21])[CH3:19]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(CCCO)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(CCCOS(C)(=O)=O)cc1

Procedure:
Following the procedure described in example 1§B, but starting from 3-(4-methylphenyl)propan-1-ol (6.02 g), triethylamine (2.9 mL), methanesulfonyl chloride (3.67 mL) and dichloromethane (39 mL), affords 3-(4-methylphenyl)propan-1-ol mesylate (3.4 g) used without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]([OH:8])[C:5]2[S:9][CH:10]=[CH:11][C:4]=2[CH2:3]1.F[C:13]1[CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:17][CH:18]=1>>[CH3:1][N:2]1[CH2:7][CH:6]([O:8][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:5]2[S:9][CH:10]=[CH:11][C:4]=2[CH2:3]1
Reactant: CN1Cc2ccsc2C(O)C1
Reactant: Fc1cccc(C(F)(F)F)c1
Product: CN1Cc2ccsc2C(Oc2cccc(C(F)(F)F)c2)C1

Procedure:
The same method as in Example 1 was conducted using 5-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-7-ol (Reference Example 14) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3-fluorobenzo trifluoride instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:11][CH:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)=[O:20].C(N(C(C)C)CC)(C)C.[C:39](Cl)(=[O:41])[CH3:40].O>C(Cl)Cl>[CH3:28][O:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[C:19]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]([N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:39](=[O:41])[CH3:40])[CH2:11][C:2]1([CH3:29])[CH3:1])=[O:20]
Reactant: CC(=O)Cl
Reactant: COc1cccc(C(=O)N2c3ccccc3C(Nc3ccccc3)CC2(C)C)c1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(C(=O)N2c3ccccc3C(N(C(C)=O)c3ccccc3)CC2(C)C)c1

Procedure:
To a solution of (2,2-dimethyl-4-phenylamino-3,4-dihydro-2H-quinolin-1-yl)-(3-methoxy-phenyl)-methanone in methylene chloride (5 mL) was added diisopropylethylamine followed by acetyl chloride. The mixture was sturred at room temperature over night. The mixture was poured into water and extracted with dichloromethane. The extracts were washed with 1 M (aq) NaOH and brine, dried over magnesium sulfate, filtered, dried and concentrated. The crude residue was purified by silica gel chromatography (50% hexanes/50% ethyl acetate) to afford N-[1-(3-methoxy-benzoyl)-2,2-dimethyl, 1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-acetamide.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH2:3]1.[Br:12]N1C(=O)CCC1=O>CN(C=O)C.C(Cl)Cl>[Br:12][C:10]1[CH:9]=[CH:8][C:7]2[N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]=2[CH:11]=1
Reactant: CN1CCOc2ccccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCOc2cc(Br)ccc21
Temperature: 80 °C
Yield: 77.5 %

Procedure:
A mixture of the 104B (0.225 g, 1.51 mmol) and N-bromosuccinimide (0.269 g, 1.51 mmol) in DMF (10 mL) was heated at 80° C. overnight. The reaction mixture was dissolved in DCM and washed with water several times. The organic layer was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 0.267 g (78%) of 104C. HPLC retention time=3.32 min. (Condition B) and LC/MS M+1=230.03 (d). 1H-NMR (500 MHz, CDCl3) δ 2.83 (s, 3H), 3.22 (t, 2H), 4.26 (t, 2H), 6.49 (d, 1H, J=8.8 Hz), 6.87 (s, 1H), and 6.90 (d, 1H, J=8.8 Hz).
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]1[CH2:14][N:13]([C:15]([O:17]C(C)(C)C)=O)[C@H:12]([C:22]([OH:24])=O)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([N:33]=C=O)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH2:36]([NH:43][CH3:44])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:25]([NH:33][C:15]([N:13]1[CH2:14][C:10](=[N:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:11][C@H:12]1[C:22]([N:43]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH3:44])=[O:24])=[O:17])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccccc2)C[C@H]1C(=O)O
Reactant: CNCc1ccccc1
Product: CN(Cc1ccccc1)C(=O)[C@@H]1CC(=NOCc2ccccc2)CN1C(=O)NC(=O)c1ccccc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, benzoyl isocyanate, and N-benzyl-N-methylamine the title compound was obtained in 40% purity by LC/MS. MS(ESI+): m/z=485.4.
Reaction SMILES: [OH:1][CH:2]=[C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]([O:6][CH3:7])=[O:5].[C:22](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.O>CN(C=O)C>[CH3:22][O:1]/[CH:2]=[C:3](\[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)/[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C(=CO)c1ccccc1OCc1ccccc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: CO/C=C(/C(=O)OC)c1ccccc1OCc1ccccc1
Yield: 17 %

Procedure:
The crude methyl 3-hydroxy-2-(2'-benzyloxyphenyl)propenoate was dissolved in dry DMF (100 ml) and potassium carbonate (29.0 g) was added in one portion. Dimethyl sulphate (16.00 g) in dry DMF (10 ml) was then added dropwise with stirring. After ninety minutes, water (300 ml) was added and the solution was extracted with ether (2×300 ml). After washing with water (3×150 ml) and brine, the extracts were dried and concentrated under reduced pressure, and the resulting yellow oil solidified on trituation with ether/petrol. Recrystallization from dry methanol afforded E-methyl 3-methoxy-2-(2'-benzyloxyphenyl)propenoate as a white, crystalline solid (5.44 g, 17% yield from methyl 2-bemnzyloxyphenylacetate), M.P. 76°-77° C.; infrared maxima (nujol mull): 1710, 1640 cm-1 ; 1H nmr (CDCl3, 90 MHz): delta 3.63 (3H, s), 3.75 (3H, s), 5.05 (2H, s), 6.80-7.40 (9H, m), 7.50 (1H, s) ppm.
Reaction SMILES: C(N(CC)CC)C.[C:8]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[CH2:13][CH:12]1[C:21]([NH2:23])=O)(=[O:10])[CH3:9].ClC(Cl)(Cl)C(Cl)=O>ClCCl>[C:8]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[CH2:13][CH:12]1[C:21]#[N:23])(=[O:10])[CH3:9]
Reactant: CC(=O)N1c2ccc(Cl)cc2CC1C(N)=O
Agent: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1c2ccc(Cl)cc2CC1C#N
Temperature: 0 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
Triethylamine (0.41291 mole) was added to intermediate (8) (0.08258 mole) suspended in dichloromethane (500 ml) at 0° C. Trichloroacetyl chloride (0.20645 mole) was added over 10 minutes. When the reaction appeared sluggish, an additional portion of triethylamine (20 ml) and then more trichloroacetyl chloride (7.6 ml) were added, and the mixture was stirred for 2 hours at low temperature. The ice bath was removed, and the mixture was allowed to sit for 2 hours. This resulted in a darker colored reaction, which was re-cooled to 0° C. Ice cold water (150 ml) was slowly added, and the mixture was stirred for 5 minutes. The layers were separated, and the organic phase was washed (ice cold 3N HCl, saturated NaHCO3), dried, filtered, and concentrated. The residue was triturated in ice cold diethylether (40 ml). Filtration, rinsing with ice cold diethylether (10 ml), yielding 15.13 g of 1-acetyl-5-chloro-2,3-dihydro-1H-indole-2-carbonitrile (intermediate 9, mp. 140–142° C.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([OH:22])=O)[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[Cl:36][C:37]1[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1[CH2:39][NH2:40]>CC(C)=O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[C:20]([NH:40][CH2:39][C:38]1[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=1[Cl:36])=[O:22])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: CCOC(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)NCc1ccccc1Cl
Temperature: 25 °C

Procedure:
To a solution of N-(t-butoxycarbonyl)tryptophan (21.28 g, 70 mmol) in 140 ml of acetone was added triethylamine (9.76 ml, 7.08 g, 70 mmol) in a portionwise manner. The resulting mixture was stirred for about thirty-five minutes at room temperature and then stirred at 45° C. for 30 minutes under nitrogen. To the resulting mixture ethyl chloroformate (7.35 ml, 8.36 g, 77 mmol) was added with continued cooling and the reaction mixture was stirred for about one hour. Next, 2-chlorobenzylamine (9.30 ml, 10.9 g, 77 mmol) was added and the reaction mixture was then stirred until a white precipitate formed. The ice bath was removed and additional acetone was added. The reaction mixture was then stirred overnight.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C@H:16]3[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[H-].[Na+].Br[CH2:26][CH:27]=[CH:28][CH3:29]>CN(C=O)C>[CH2:26]([O:22][C@H:19]1[CH2:18][CH2:17][C@H:16]([C@H:13]2[CH2:14][CH2:15][C@H:10]([C@H:7]3[CH2:6][CH2:5][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:9][CH2:8]3)[CH2:11][CH2:12]2)[CH2:21][CH2:20]1)[CH:27]=[CH:28][CH3:29]
Reactant: CC=CCBr
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H]([C@H]3CC[C@H](O)CC3)CC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC=CCO[C@H]1CC[C@H]([C@H]2CC[C@H]([C@H]3CC[C@H](CCC)CC3)CC2)CC1
Temperature: 25 °C

Procedure:
To a solution of 10.0 g (33.1 mmol) of trans-4-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)cyclohexanol in 100 ml of DMF was added dropwise, while stirring the solution at room temperature, a suspension of 1.19 g (49.6 mmol) of NaH in 10 ml of DMF. After completion of the dropwise addition, the reaction mixture was stirred for 2 hours and then the temperature of the reaction mixture was gradually allowed to rise up to about 80° C. and a solution of 5.35 g (39.7 mmol) of 1-bromo-2-butene in 20 ml of DMF was added dropwise. After completion of the dropwise addition, the mixture was heated under reflux at the same temperature for 5 hours. After the reaction solution was allowed to cool down to room temperature, the reaction product was poured into an ice-water and extracted with 500 ml of toluene. The organic layer was washed three times with water, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. A silica gel column chromatography (developing solvent: toluene) of the residue gave 5.96 g of crude 1-(2-butenyloxy)-trans-4-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)cyclohexane.