Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:13]([S:14](Cl)(=[O:16])=[O:15])=[C:12]([Cl:18])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:26]([O:30][C:31](=[O:38])[NH:32][C@@H:33]1[CH2:37][CH2:36][NH:35][CH2:34]1)([CH3:29])([CH3:28])[CH3:27]>C1COCC1>[C:26]([O:30][C:31](=[O:38])[NH:32][C@@H:33]1[CH2:37][CH2:36][N:35]([S:14]([C:13]2[C:7]3[O:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:9][C:8]=3[CH:10]=[CH:11][C:12]=2[Cl:18])(=[O:16])=[O:15])[CH2:34]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1nc2ccc(Cl)c(S(=O)(=O)Cl)c2o1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(S(=O)(=O)c2c(Cl)ccc3nc(C(C)(C)C)oc23)C1
Yield: 67.3 %

Procedure:
Following the general procedure for the synthesis of sulfonylamides outlined in example 51, 2-tert-butyl-6-chloro-benzooxazole-7-sulfonyl chloride (3.0 g, 9.74 mmol), triethylamine (1.63 mL, 11.7 mmol), and (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (2.18 g, 11.7 mmol) were reacted in THF (30 mL) to afford the title compound (3.0 g, 67%). 1H NMR (CDCl3) • 7.77 (d, 1H, J=8.5 Hz), 7.48 (d, 1H, J=8.5 Hz), 4.67 (bm, 1H), 4.22 (bm, 1H), 3.66 (bm, 2H), 3.52 (bm, 1H), 3.41 (bm, 1H), 2.19 (bm, 1H), 1.90 (bm, 1H), 1.48 (s, 9H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:20]I.N1C=CN=C1.[CH2:27]([O:34][C:35](=[O:49])[NH:36][C@H:37]([CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38]O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(Cl)Cl>[CH2:27]([O:34][C:35](=[O:49])[NH:36][C@H:37]([CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][I:20])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)NC[C@H](CO)NC(=O)OCc1ccccc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@H](CI)NC(=O)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
Triphenylphosphine bound to cross-linked polystyrene resin (0.82 g, 3 mmol/g, 2.47 mmol) is suspended in dry DCM (10 ml) at ambient temperature under a nitrogen atmosphere. Iodine (0.62 g, 2.47 mmol) is added and the reaction mixture stirred for 15 minutes. Imidazole (0.167 g, 2.47 mmol) is then added and the reaction mixture is stirred for a further 15 minutes. A solution of [(R)-1-(tert-butoxycarbonylamino-methyl)-2-hydroxy-ethyl]-carbamic acid benzyl ester (0.401 g, 1.23 mmol) in dry dichloromethane (5 ml) is added and the reaction mixture is stirred at reflux for 1.5 hour. The polymer is removed by filtration, and the filtrate is first washed with aqueous 5% sodium thiosulphate solution and then water. The organic phase is dried over MgSO4 and evaporated to yield [(R)-1-(tert-butoxycarbonylamino-methyl)-2-iodo-ethyl]-carbamic acid benzyl ester. [MH]+ 435.0.
Reaction SMILES: [Si](I)(C)(C)C.C[C@:7]([NH:35]C(OC(C)(C)C)=O)([CH2:11][S:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27]3)=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[C:8]([O-:10])=[O:9].[C:43](=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:43][O:10][C:8](=[O:9])[C@@H:7]([NH2:35])[CH2:11][S:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27]3)=[CH:22][CH:21]=2)=[CH:16][CH:15]=1
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N[C@@](C)(CSCc1ccc(-c2ccc(-n3ccc4ccccc43)cc2)cc1)C(=O)[O-]
Agent: C[Si](C)(C)I
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@H](N)CSCc1ccc(-c2ccc(-n3ccc4ccccc43)cc2)cc1
Reaction time: 0.17 h
Yield: 95 %

Procedure:
TMSI (1.56 mL, 10.63 mmol) was added dropwise to a stirred solution of (2R)-methyl-tert-butoxycarbonylamino-3-(4′-indol-1-ylbiphen-4-ylmethylsulfanyl)-propionate (4.47 g, 8.66 mmol) in anhydrous methylene chloride (50 mL). The reaction was stirred for 10 mins. and then poured into 1N sodium bicarbonate solution (50 mL), extracted with ethyl acetate (3×50 mL). The combined extract was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 5% methanol in methylene chloride as eluent, afforded the title compound as a yellow oil (3.43 g, 95%):. Rf=0.65 (10% methanol in dichloromethane). 1H NMR (DMSO-d6, 300 MHz): δ 7.86 (2H, d, J=8 Hz, Ar—H), 7.64-7.72 (6H, m, Ar—H), 7.61 (1H, d, J=8 Hz, , Ar—H), 7.42 (1H, d, J=8 Hz, Ar—H), 7.21 (1H, td, J=7, 2 Hz, Ar—H), 7.14 (1H, td, J=7, 2 Hz, Ar—H), 6.72 (1H, d, J=3.5 Hz, Ar—H), 3.80 (2H, s, PhCH2), 3.62 (3H, s, OMe), 3.56 (1H, t, J=6.5 Hz, CHN), 2.68 (1H, dd, J=6.5, 3 Hz, CHHCHN), 2.63 (1H, dd, J=6.5, 3 Hz, CHHCHN), 2.04 (2H, br s, NH2).
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([N:14]2[CH2:19][CH2:18][CH2:17][C@@H:16]([CH3:20])[C@H:15]2[CH2:21][NH2:22])=[O:13])[N:3]=[CH:4][CH:5]=1.Cl[C:24]1[O:25][C:26]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:27]=2[N:28]=1>>[N:1]1[N:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([N:14]2[CH2:19][CH2:18][CH2:17][C@@H:16]([CH3:20])[C@H:15]2[CH2:21][NH:22][C:24]2[O:25][C:26]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:27]=3[N:28]=2)=[O:13])[N:3]=[CH:4][CH:5]=1
Reactant: C[C@@H]1CCCN(C(=O)c2ccccc2-n2nccn2)[C@@H]1CN
Reactant: Clc1ccc2oc(Cl)nc2c1
Product: C[C@@H]1CCCN(C(=O)c2ccccc2-n2nccn2)[C@@H]1CNc1nc2cc(Cl)ccc2o1

Procedure:
The title compound was prepared following the same general protocol as described for Example A2 using (2-(2H-1,2,3-triazol-2-yl)phenyl)((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)methanone and 2,5-dichlorobenzoxazole. MS (ESI) 451 (M+H).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:8]=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[C:20]([N:27]1[CH2:32][CH2:31][CH2:30][C:29](=[O:33])[CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>C1COCC1>[C:1]([C:5]1[N:9]([CH2:10][CH2:11][CH2:12][O:13][CH3:14])[C:8]([C:29]2([OH:33])[CH2:30][CH2:31][CH2:32][N:27]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:28]2)=[N:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCCn1cncc1C(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCCn1c(C(C)(C)C)cnc1C1(O)CCCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 21.3 %

Procedure:
Into a 50 mL round bottomed flask was added 5-tert-butyl-1-(3-methoxypropyl)-1H-imidazole (133A) (376 mg, 1.9 mmol) and THF (9.6 mL). The solution was cooled to −78° C. and n-BuLi (843 μL, 2.5 M/hexanes, 2.1 mmol) was added slowly via syringe. The mixture was stirred for 20 minutes and slowly warmed to −30° C. The solution was cooled to −78° C. and N-Boc-3-piperidone (418 mg, 2.1 mmol) in THF (5 mL) was added slowly via syringe; the mixture was allowed to warm to room temperature overnight. Solvent was removed under vacuum and the residue was partitioned between water (25 mL) and ethyl acetate (25 mL). The organic layer was separated and discarded. The aqueous layer extracted with ethyl acetate (2×25 mL). The organic portions were combined and washed with brine (50 mL) and dried over sodium sulfate and filtered. The solvent was removed in vacuo and the residue was purified by preparatory LC/MS (10-45% CH3CN in H2O) to give tert-butyl 3-(5-tert-butyl-1-(3-methoxypropyl)-1H-imidazol-2-yl)-3-hydroxypiperidine-1-carboxylate (133B) as a yellow oil (160 mg, 21% yield). ESI-MS:m/z 396.5 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH2:9][C:10](N)=[O:11])=[C:4]([F:13])[CH:3]=1.[OH-:14].[Na+].Cl>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH2:9][C:10]([OH:14])=[O:11])=[C:4]([F:13])[CH:3]=1
Reactant: [OH-]
Reactant: NC(=O)Cc1c(F)cc(Br)cc1F
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)Cc1c(F)cc(Br)cc1F
Temperature: 80 °C
Reaction time: 1 h
Yield: 46.3 %

Procedure:
A suspension of 2-(4-bromo-2,6-difluorophenyl)acetamide (7.20 mmol) in ethanol (10 mL) was treated with 6N aq sodium hydroxide (90 mmol) at room temperature. The vessel was then stirred in an oil bath at 80° C. After one hour the reaction mixture had turned clear. After stirring overnight, the reaction mixture was cooled to room temperature, at which point the pH was adjusted to ˜1 with 6N aq HCl. A white precipitate formed, and the solution was concentrated to a volume of ˜10 mL, at which point it was extracted three times with ethyl acetate. The combined organic layers were washed twice with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a solid (837 mg, 41% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.60 (s, 2 H) 7.49 (d, J=6.82 Hz, 2 H) 12.82 (br. s., 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][S:7][C:8]([N:10]2[C@H:22]([C:23]([OH:25])=[O:24])[CH2:21][C:20]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:12]=3[CH2:11]2)=[S:9])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:32]O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][S:7][C:8]([N:10]2[C@H:22]([C:23]([O:25][CH3:32])=[O:24])[CH2:21][C:20]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:12]=3[CH2:11]2)=[S:9])=[CH:26][CH:27]=1
Reactant: CO
Reactant: O=C(O)[C@@H]1Cc2c([nH]c3ccccc23)CN1C(=S)SCc1ccc(Cl)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H]1Cc2c([nH]c3ccccc23)CN1C(=S)SCc1ccc(Cl)cc1
Reaction time: 5 h
Yield: 50 %

Procedure:
(3S)-2-[(4-Chlorobenzylthio)thiocarbonyl]-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (2.08 g) is dissolved in methanol (30 ml) and thereto is added dropwise thionyl chloride (0.94 ml) at -20° C. The mixture is stirred at 50°-60° C. for 5 hours and then distilled to remove the solvent. The residue is dissolved in ethyl acetate, and the solution is washed with water, dried, treated with active carbon and distilled to remove the solvent. The residue is recrystallized from ethyl acetate-n-hexane to give the title compound (1.08 g, 50%) as colorless needles, mp 181°-182° C. (decomp.).
Reaction SMILES: [C:1]([C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH:10](O)[CH3:11])=[C:5]([O:13][CH3:14])[C:4]=1[CH:15]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1)#[N:2].S(Cl)([Cl:28])=O>C(Cl)Cl.CN(C)C=O>[Cl:28][CH:10]([C:6]1[C:5]([O:13][CH3:14])=[C:4]([CH:15]2[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]2)[C:3]([C:1]#[N:2])=[C:8]([CH3:9])[CH:7]=1)[CH3:11]
Reactant: O=S(Cl)Cl
Reactant: COc1c(C(C)O)cc(C)c(C#N)c1C1CN(C(=O)OC(C)(C)C)C1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(C(C)Cl)cc(C)c(C#N)c1C1CN(C(=O)OC(C)(C)C)C1
Reaction time: 2 h
Yield: 94.2 %

Procedure:
The tert-butyl 3-[2-cyano-5-(1-hydroxyethyl)-6-methoxy-3-methylphenyl]azetidine-1-carboxylate (2.1 g, 6.4 mmol) was taken up in methylene chloride (50.0 mL) and N,N-dimethylformamide (0.59 mL), cooled in an ice bath and the thionyl chloride (0.56 mL, 7.7 mmol) was added slowly. After stirring for 2 hrs the reaction was complete by LC/MS and was partitioned between ethyl acetate and water. The combined organic layer was washed with water saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated to give crude tert-butyl 3-[3-(1-chloroethyl)-6-cyano-2-methoxy-5-methylphenyl]azetidine-1-carboxylate as an oil (2.2 g, 100%). LCMS calculated for C15H18ClN2O3(M+H)+: m/z=309.1; found: 309.1.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=2)=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[H-].[Na+].[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>N1C=CC=CC=1.CN(C=O)C>[N+:1]([C:4]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:16]=2)=[CH:7][C:5]=1[NH:6][C:29](=[O:30])[C:28]1[CH:32]=[CH:33][C:25]([O:24][CH3:23])=[CH:26][CH:27]=1)([O-:3])=[O:2]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)c1ccc(-c2ccc([N+](=O)[O-])c(N)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(-c2ccc([N+](=O)[O-])c(NC(=O)c3ccc(OC)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.3 %

Procedure:
A suspension of 102 (599 mg, 2.20 mmol), NaH 60% (141 mg, 3.52 mmol) and 4-methoxybenzoyl chloride (450 mg, 2.64 mmol) in pyridine (5 ml) and DMF (12 ml) was stirred at room temperature during 48 h. The solid was filtered out and rinsed with MeOH to give 584 mg (82%) of the title compound 103 as a yellow solid. 1H NMR: (400 MHz, DMSO) δ (ppm): 10.72 (s, 1H), 8.13-8.08 (m, 3H), 7.96 (d, J=8.8 Hz, 2H), 7.90 (d, J=8.6 Hz, 2H), 7.74 (dd, J=8.6, 2.2 Hz, 1H), 7.11 (d, J=8.8 Hz, 1H), 3.89 (s, 3H), 3.86 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH2:9].[C:10](OC(=O)C)(=[O:12])[CH3:11].C(O)C>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:12])[CH3:11]
Reactant: Nc1ccc(I)cc1F
Reactant: CC(=O)OC(C)=O
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a stirred solution of 2-fluoro-4-iodo-phenylamine (61 g, 257 mmol) in anhydrous pyridine (25 mL) was added drop-wise acetic anhydride (32.8 mL, 321 mmol) at such a rate to maintain the internal temperature between 10° C. and 20° C. At the end of the addition, the reaction was stirred for an additional 0.5 h at rt followed by heating on an oil bath (external temperature 50–60° C.). The reaction was monitored by thin layer chromatography. Once complete (ca. 1.5 h), the mixture was cooled and the reaction mixture solidified. The solid was slurried with cold ethanol (50 mL) and filtered. The solid was washed with cold ethanol (mL) and dried to a fine white crystalline material. The filtrate was concentrated and taken up in ethanol (20 mL) and cooled overnight. Further product was obtained. 63 g (226 mmol) was isolated as a fine white, crystalline solid. Yield: 88%; mp 153° C.; 1H NMR (400 MHz, CDCl3) δ 8.15 (t, J=8 Hz, 1H), 7.33 (br s, 1H), 7.49 (m, 2H), 2.24 (s, 3H, Me).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:25])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH:20]([CH3:22])[CH3:21])[C:17](O)=[O:18])[C:10](=[O:23])[CH:9]=2)[CH:7]=1.[NH2:26][C:27]1[CH:28]=[CH:29][C:30]2[N:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[NH:32][C:31]=2[CH:40]=1.CC(C)N=C=NC(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:25])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH:20]([CH3:21])[CH3:22])[C:17]([NH:26][C:27]3[CH:28]=[CH:29][C:30]4[N:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[NH:32][C:31]=4[CH:40]=3)=[O:18])[C:10](=[O:23])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(C(=O)O)C(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CCOC(=O)c1nc2ccc(N)cc2[nH]1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2ccc(NC(=O)C(C(C)C)n3cc(OC)c(-c4cc(Cl)ccc4C#N)cc3=O)cc2[nH]1

Procedure:
100 mg (277 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-methylbutanoic acid (racemate), 57 mg (277 μmol, 1.0 eq.) of ethyl 6-amino-1H-benzimidazole-2-carboxylate, 39.4 mg (277 μmol) of Oxima and 42.9 μl (277 μmol) of DIC in 5.4 ml of dimethylformamide were reacted according to General Method 5B. The crude product was purified by flash chromatography (silica gel 50, cyclohexane/ethyl acetate mixtures). Yield: 139 mg (91% of theory)
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.[CH3:11][C:12]1([CH3:23])[CH:21]=[C:20]([CH3:22])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13]1>>[CH3:11][C:12]1([CH3:23])[CH2:21][CH:20]([CH3:22])[CH:19]2[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18]2)[NH:13]1
Reactant: CC1=CC(C)(C)Nc2ccccc21
Solvent: c1ccc2ncccc2c1
Product: CC1CC(C)(C)NC2CCCCC12

Procedure:
The dimer of 2,2,4-trimethyldecahydroquinoline was prepared by hydrogenation of the dimer of the unsaturated quinoline. In the process of preparing 2,2,4-trimethyl-1,2-dihydroquinoline (TMDQ) an amount of the dimer product is also formed. This TMDQ dimer can be separated out of the TMDQ and itself used to prepare substituted decahydroquinolines of the invention. 6-[4'-(2,2,4-trimethyl-1,2-dihydroquinolyl)]-2,2,4-trimethyl-1,2-dihydroquinoline was obtained by distillation and separation of the chemical from the reaction mix of a 2,2,4-trimethyl-1,2-dihydroquinoline preparation. The chemical had a boiling point of 198° C. at 1.3 mm Hg. The chemical was placed in an autoclave with hydrogen and a catalyst of rhodium at 5% by weight on charcoal. Reaction temperature was 210° C. and internal pressure was 2000 psig. After 24 hours, the reaction mix was cooled down, the catalyst filtered out, and the liquid subjected to distillation. A liquid fraction boiling at 190° C. at 1 mm Hg was collected and analyzed. The IR spectra and NMR spectra of the liquid was consistent with the desired product, 6-[4'-(2,2,4-trimethyldecahydroquinolyl)]-2,2,4-trimethyldecahydroquinoline. The calculated carbon, hydrogen, nitrogen content of the C24H44N2 compound is 79.93% carbon, 12.30% hydrogen, and 7.77% nitrogen while the analyzed contents were 80.30% carbon, 12.43% hydrogen, and 7.63% nitrogen.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH2:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.Cl[C:15]([C:17]12[CH2:24][CH2:23][CH2:22][N:21]1[CH2:20][CH2:19][CH2:18]2)=[O:16]>N1C=CC=CC=1>[NH2:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[NH:1][C:15]([C:17]12[CH2:24][CH2:23][CH2:22][N:21]1[CH2:20][CH2:19][CH2:18]2)=[O:16]
Reactant: Nc1cnc2ccccc2c1N
Reactant: O=C(Cl)C12CCCN1CCC2
Agent: Cl
Solvent: c1ccncc1
Product: Nc1c(NC(=O)C23CCCN2CCC3)cnc2ccccc12
Yield: 41.8 %

Procedure:
In 330 ml of pyridine was dissolved 5.52 g (34.7 mmol) of 3,4-diaminoquinoline. To the solution was slowly added 7.70 g (36.5 mmol) of 5-chlorocarbonyl-1-azabicyclo[3.3.0]octane hydrochloride while stirring at -15° to 20° C., followed by stirring at 15 to 20° C. for 16 hours. The reaction mixture was concentrated under reduced pressure, and 100 ml of a saturated sodium hydrogen-carbonate aqueous solution was added to the residue. The mixture was extracted with 800 ml of chloroform. The extract was washed with 40.0 ml of a sodium chloride aqueous solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by alumina column chromatography to obtain 4.30 g (yield: 41.8%) of the titled compound as an oil. The resulting oil was crystallized from ethanol-diethyl ether to obtain 3.05 g of the titled compound as a pale yellow prism.
Reaction SMILES: [F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([N:40]2[CH2:44][CH2:43][N:42]([C:45]3[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=3)[C:41]2=[O:52])=[O:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:32]=[CH:31][C:17]([CH2:18][N:19]([CH2:27][CH2:28][O:29][CH3:30])C(=O)OC(C)(C)C)=[CH:16][CH:15]=3)[S:13][C:6]=12.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([N:40]2[CH2:44][CH2:43][N:42]([C:45]3[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=3)[C:41]2=[O:52])=[O:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:18][NH:19][CH2:27][CH2:28][O:29][CH3:30])=[CH:31][CH:32]=3)[S:13][C:6]=12
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)N5CCN(c6ccc(F)cc6)C5=O)cc4F)c3s2)cc1)C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)N5CCN(c6ccc(F)cc6)C5=O)cc4F)c3s2)cc1
Yield: 135.6 %

Procedure:
A solution of 223 (60 mg, 0.082 mmol) and TFA (1 mL) in toluene (2 mL) was stirred 30 min at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was triturated with diethyl ether, the solid was collected and dried to give the title compound 220 (70 mg, 99.5%) as an off-white solid. 1H NMR (DMSO-d6) δ (ppm): 10.55 (s, 1H), 8.95 (s, broad, 2H), 8.52 (d, J=5.5 Hz, 1H), 8.13 (s, 1H), 7.97 (d, J=8.4 Hz, 2H), 7.84 (dd, J=2.5 and 13.1 Hz, 1H), 7.65-7.61 (m, 4H), 7.49 (t, J=8.8 Hz, 1H), 7.44 (dd, J=2.4 and 8.8 Hz, 1H), 7.30-7.25 (m, 2H), 6.65 (d, J=5.5 Hz, 1H), 4.21 (t, 1H), 3.93 (m, 4H), 3.57 (t, 2H), 3.30 (s, 3H), 3.11 (m, 2H). MS (m/z): 630.3 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])[CH2:21][CH:20]3[OH:35])=[CH:15][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:37][C:38]1[CH:39]=[CH:40][C:41]2[O:46][CH2:45][C:44](=[O:47])[N:43]([CH2:48][CH2:49][CH2:50][O:51][CH3:52])[C:42]=2[CH:53]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[CH:15][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[O:26])[CH2:21][CH:20]3[O:35][CH2:37][C:38]3[CH:39]=[CH:40][C:41]4[O:46][CH2:45][C:44](=[O:47])[N:43]([CH2:48][CH2:49][CH2:50][O:51][CH3:52])[C:42]=4[CH:53]=3)=[CH:17][CH:18]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(C3CCN(C(=O)OCc4ccccc4)CC3O)cc2)C1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OC4CN(C(=O)OC(C)(C)C)C4)cc3)cc21

Procedure:
Analogously to Method D, 13.34 g of benzyl 4-[4-(1-tert-butoxycarbonylazetidin-3-yloxy)phenyl]-3-hydroxypiperidine-1-carboxylate and 8.267 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benz[1,4]oxazin-3-one are reacted. The title compound is obtained as a yellow oil. Rf=0.33 (2:1 EtOAc-heptane); Rt=5.53.
Reaction SMILES: O.[C:2](Cl)(Cl)=[S:3].[NH2:6][C:7]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10]>C(Cl)Cl>[C:9]([C:8]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:7]=1[N:6]=[C:2]=[S:3])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cc(Cl)ccc1N=C=S

Procedure:
A five liter, 3-necked, round-bottom flask equipped with a condenser plus scrubber, mechanical stirrer, and dropping funnel was used as the reaction vessel. The reaction vessel was cooled in an ice bath after charging with 1.2 liters of water. After the water had cooled, 126 ml (1.65 moles) of thiophosgene was added. The mixture was stirred vigorously while a solution containing 352 grams (1.52 moles) of 2-amino-5-chlorobenzophenone in about 1 liter of methylene chloride was added over a period of 20 to 25 minutes. After addition was complete the funnel was rinsed with about 150 ml of methylene chloride and the reaction mixture was stirred for about one hour with the ice bath in place. Then the ice bath was removed and the reaction mixture was stirred for one additional hour. The organic phase was separated, dried with magnesium sulfate, and concentrated in vacuo. The 2-benzoyl-4-chlorophenylisothiocyanate remained behind as a brown oil which solidified on cooling. The product was recrystallized from hexane to yield tan crystals.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.[H-].[Na+].[CH2:15]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[CH2:15]([C:22]1[CH:23]=[CH:24][C:25]([C:26]([NH:1][C:2]2[S:3][C:4]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=2)=[O:27])=[CH:29][CH:30]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCNC(=O)c1sc(N)nc1C
Reactant: O=C(Cl)c1ccc(Cc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: CCNC(=O)c1sc(NC(=O)c2ccc(Cc3ccccc3)cc2)nc1C
Temperature: 25 °C

Procedure:
To a solution of 2-amino-N-ethyl-4-methylthiazole-5-carboxamide (0.17 g, 0.93 mmol) in dichloromethane (2 mL) at −78° C. was added sodium hydride (excess) followed by the addition of 4-benzylbenzoyl chloride (1 equiv of 0.5 M in N,N-dimethylformamide). The reaction was allowed to warm to ambient temperature over 18 h then concentrated in vacuo. The crude product was purified by preparative HPLC (acetone/water gradient) to afford the title compound (0.005 g); 1H NMR (CD3OD, 400 MHz) δ 7.90 (d, J=8.6 Hz, 2H), 7.35 (d, J=8.1 Hz, 2H), 7.27-7.13 (m, 5H), 4.03 (s, 2H), 3.32 (q, J=7.6 Hz, 2H), 2.50 (s, 3H), 1.17 (t, J=7.6 Hz, 3H); MS (ES+) m/z 380 (M+1).