Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C@H:6]([NH2:13])[CH2:7]2.CO[CH:16](OC)[CH:17]=O.[S-:21][C:22]#[N:23].[K+]>C(O)C.[Pd].Cl>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([N:13]1[CH:16]=[CH:17][NH:23][C:22]1=[S:21])[CH2:7]2
Reactant: N#C[S-]
Reactant: N[C@H]1CCc2c(F)cc(F)cc2C1
Reactant: COC(C=O)OC
Agent: [Pd]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: Fc1cc(F)c2c(c1)CC(n1cc[nH]c1=S)CC2
Yield: 42.5 %

Procedure:
A mixture of (S)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-ylamine (2.05 g, 11.2 mmol), prepared as in Example 8, and dimethoxyacetaldehyde (1.73 g, 13.1 mmol) in 50 mL of ethanol was hydrogenated over 10% palladium on carbon (500 mg) for 18 hours. The mixture was filtered and concentrated by evaporation. The residue was combined with potassium thiocyanate (1.57 g, 16.2 mmol) in 30 mL of 1N hydrochloric acid and 20 mL of ethanol and the mixture was heated at 70°-80° C. for 18 hours. The mixture was cooled in an ice bath giving a crystalline material which was isolated by filtration. Recrystallization from ethyl acetate/hexane gave 1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione (1.27 g, 4.76 mmol), m.p. 250°-251° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35])[O:12][CH2:13][C:14](=[O:27])[N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1.[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[C:40]([O:48][C:49]([F:52])([F:51])[F:50])[CH:39]=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:44]([C:41]1[CH:42]=[CH:43][C:38]([O:37][CH3:36])=[CH:39][C:40]=1[O:48][C:49]([F:50])([F:51])[F:52])(=[O:46])=[O:45])[C:6](=[O:11])[C:5]2([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35])[O:12][CH2:13][C:14](=[O:27])[N:15]1[CH2:16][CH2:17][N:18]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH2:19][CH2:20]1
Reactant: COc1ccccc1C1(OCC(=O)N2CCN(c3cccnc3)CC2)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(OCC(=O)N3CCN(c4cccnc4)CC3)(c3ccccc3OC)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Product: Cl

Procedure:
With 300 mg of the compound obtained in Step 55-1 and 201 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 262 mg of free form of the title compound (yellow amorphous) was obtained by a similar method to Example 2. In a similar procedure to Example 43, by subjecting 237 mg of the obtained free form to salt formation and solidification, 211 mg of the title compound (colorless amorphous) was obtained.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[N:24]1C(=O)C(=CC2C=CC=CC=2)S[C:25]1=[S:37])(=O)C.[CH2:38]([NH:40][CH2:41][CH3:42])[CH3:39]>CO>[C@@H:6]1([NH:24][C:25]([N:40]([CH2:41][CH3:42])[CH2:38][CH3:39])=[S:37])[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](N2C(=O)C(=Cc3ccccc3)SC2=S)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCNCC
Solvent: CO
Product: CCN(CC)C(=S)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 21 h

Procedure:
N-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-5-benzylidenerhodanine (1.102 g., 0.002 mole) was added to a solution of diethylamine (1.76 g., 0.024 mole) in 50 ml. of methanol in a pressure bottle. The reaction mixture was stirred at room temperature for 21 hours in the pressure bottle with the stopper well closed. The mixture was filtered and the filtrate was evaporated to a brownish syrupy material below 30° in vacuo. The residue was dissolved in the minimum amount of acetone, and anhydrous ether was added to the solution to give a sticky solid. The supernatant was decanted, and the residual solid was dried at room temperature in vacuo. The solid was partially dissolved in ethyl acetate to give a slurry, and chromatographed on a column of silica gel (1×20 cm) using ethyl acetate as the first solvent (60 ml.) and acetone as the second solvent (100 ml.). The 100 ml. of acetone effluent was reduced to ca. 25 ml. and was set aside at room temperature. The beige crystalls were filtered, washed with acetone, and dried at room temperature in vacuo, yielding 0.51 g. (81.5%); m.p. 106°-109°(dec.)
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[OH:34]>CC#N>[Br-:23].[OH:10][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:24][CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[OH:34])([CH2:2][CH2:3]1)[CH2:8][CH2:7]2
Reactant: Oc1ccccc1OCCCBr
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Solvent: CC#N
Product: Oc1ccccc1OCCC[N+]12CCC(C(O)(c3ccccc3)c3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 74.8 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct -4-yl(diphenyl)methanol (0.0505 g, 0.172 mmol) and 2-[(3-bromopropyl)oxy]phenol (0.0547 g, 0.236 mmol) in 2 CH3CN/3CHCl3 (4.0 mL) were reacted to give the desired product (0.0675 g, 75.0%). EI-MS m/z 444(M+) Rt (1.91 min).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]2[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][C:33]=2[CH3:39])[CH2:26][C:27]([O:29]CC)=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=1.[Li+].[OH-].C(O)(C(F)(F)F)=O>O.CC#N>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]2[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][C:33]=2[CH3:39])[CH2:26][C:27]([OH:29])=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(NC=NN)c1)c1cc(C)ccc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Cc1ccc(C)c(C(CC(=O)O)NC(=O)CNC(=O)c2cccc(NC=NN)c2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 87.8 %

Procedure:
To the product from Example 180 (710 mg, 0.0013 mole) in H2O (10 mL) and CH3CN (10 mL) was added LiOH (215 mg, 0.005 mole). The reaction mixture was stirred at room temperature for 2.5 hours. The pH was lowered to ~3 with TFA and the product was isolated by RPHPLC to yield the title compound (600 mg after lyophilization) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.N([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=C=O.C(N(C(C)C)C(C)C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[CH3:20][CH2:19][CH:18]([C:8]([NH2:7])=[O:9])[CH2:17][CH2:16][CH3:15]
Reactant: CCCCCCN=C=O
Agent: O=c1[nH]c2cc(Cl)ccc2o1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCC(CC)C(N)=O

Procedure:
100 mg (0.59 mmol) of 5-chloro-3H-benzooxazol-2-one were reacted in analogy to Example 1 with 112.6 mg (0.885 mmol) of 1-isocyanatohexane in the presence of ethyldiisopropylamine in THF at 70° C. Yield: 125 mg (71%), M+H+: 297.1.
Reaction SMILES: Cl[C:2]([O:5]C(Cl)=O)(Cl)Cl.N1C2C(=CC=CC=2)C=CC=1.[F:19][C:20]1[CH:53]=[C:52]([F:54])[C:51]([F:55])=[CH:50][C:21]=1[CH2:22][O:23][CH2:24][C@@H:25]1[CH2:29][C@@H:28]([S:30][C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:27][NH:26]1.[C:56]([O:65][CH3:66])(=[O:64])[C:57]1[C:58](=[CH:60][CH:61]=[CH:62][CH:63]=1)[OH:59].[H-].[Na+]>C(Cl)Cl>[CH3:66][O:65][C:56]([C:57]1[CH:63]=[CH:62][CH:61]=[CH:60][C:58]=1[O:59][C:2]([N:26]1[CH2:27][C@H:28]([S:30][C:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:29][C@H:25]1[CH2:24][O:23][CH2:22][C:21]1[CH:50]=[C:51]([F:55])[C:52]([F:54])=[CH:53][C:20]=1[F:19])=[O:5])=[O:64]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Fc1cc(F)c(COC[C@@H]2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2)cc1F
Reactant: COC(=O)c1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: c1ccc2ncccc2c1
Solvent: ClCCl
Product: COC(=O)c1ccccc1OC(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1COCc1cc(F)c(F)cc1F
Temperature: 25 °C
Yield: 125.1 %

Procedure:
A solution of 0.07 ml (0.55 mmol) trichloromethyl-chloroformate in 7 ml CH2Cl2 was treated at 0° C. with 0.13 ml (1.1 mmol) quinoline and after 15 min with 0.52 g (1 mmol) (2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine in 7 ml CH2Cl2. After 2 h at 0° C. the CH2Cl2 was evaporated. The residue was dissolved in 15 ml THF, treated at 0° C. with 0.27 ml (2.1 mmol) methyl salicylate, 96 mg (2.4 mmol) of 55% NaH and 166 mg (1 mmol) of KI. The reaction was stirred at room temperature over night, cooled (0° C.) and after the addition of 44 mg (1 mmol) of 55% NaH refluxed for 3 h. The reaction was partitioned between aqueous 10% KHSO4/EtOAc (3×300). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and evaporated. Flash chromatography on silica gel (Hexane/EtOAc 9:1) gave 0.48 g (69%) (2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid 2-methoxycarbonyl-phenyl ester, MS: 698 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].Cl[C:12]([O:15]C(=O)OC(Cl)(Cl)Cl)(Cl)Cl.O1CCOCC1>CO>[Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([F:10])[C:3]=1[N:4]=[C:12]=[O:15]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1c(F)cc(Cl)cc1Br
Solvent: CO
Solvent: C1COCCO1
Product: O=C=Nc1c(F)cc(Cl)cc1Br
Temperature: 100 °C

Procedure:
2-Bromo-4-chloro-6-fluoroaniline (5 mmol, 1.125 g), bis(trichloromethyl)carbonate (1.7 mmol, 0.50 g) and 1,4-dioxane (10 ml) were mixed together and the mixture was heated to 100° C. for 15 minutes; the mixture was then cooled to room temperature and it was filtered. The filtrate was concentrated to afford a mixture of products (2.2 g) containing the title compound, M++MeO=283 (LC-MS run in methanol).
Reaction SMILES: [CH2:1]([S:3][C:4]#[N:5])[CH3:2].O=[C:7]([CH2:26][CH2:27][CH2:28][CH3:29])[CH:8]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1.O.[OH-].[NH4+]>P(Cl)(Cl)(Cl)=O>[CH2:26]([C:7]1[N:5]=[C:4]([S:3][CH2:1][CH3:2])[C:21]2[C:20]([C:8]=1[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:18][CH:19]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCC(=O)C(Cc1ccc(C(=O)OC)cc1)c1ccccc1
Reactant: CCSC#N
Agent: [NH4+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCCCc1nc(SCC)c2ccccc2c1Cc1ccc(C(=O)OC)cc1
Reaction time: 10 h

Procedure:
0.4 ml of ethyl thiocyanate and 0.45 ml of stannic chloride were added to a solution of 1 g of methyl 4-(3-oxo-2-phenyl-heptyl) benzoate of Step C in 20 ml of phosphorous oxychloride and the mixture was stirred for 10 hours at reflux, then poured into ice-cooled water. The mixture was stirred for 15 minutes and alkalized with concentrated ammonium hydroxide. Extraction was carried out with ethyl acetate and the extracts were washed with water, dried and evaporated to dryness. The residue was chromatographed on silica (eluant: hexane - ethyl acetate (9-1)) to obtain 0.57 g of the desired product melting at 70° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([N:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH:31]1[CH3:37])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C>CC(O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:36][C@H:33]4[CH2:34][CH2:35][N:30]([CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C@@H:31]([CH3:37])[CH2:32]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:36][C@@H:33]4[CH2:34][CH2:35][N:30]([CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[C@@H:31]([CH3:37])[CH2:32]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1CC(N)CCN1Cc1ccccc1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1C[C@@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CCN1Cc1ccccc1
Product: C[C@H]1C[C@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CCN1Cc1ccccc1
Yield: 65 %
Yield: 21 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (1.01 g, 3.00 mmol), 1-benzyl-2-methyl-piperidin-4-ylamine (674 mg, 3.30 mmol) and diisopropylethylamine (1.83 mL, 10.5 mmol) in propan-2-ol (30 mL) was heated to reflux for 1 hour. The mixture was filtered through Celite® and the filtrate concentrated under vacuum. Purification by column chromatography on silica gel (gradient: 0 to 30% ethyl acetate in toluene) afforded 990 mg (65%) of racemic cis (1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-(1-benzyl-2-methyl-piperidin-4-yl)-amine as a yellow foam and 320 mg (21%) of racemic trans (1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-(1-benzyl-2-methyl-piperidin-4-yl)-amine as a yellow foam. Analysis for racemic cis: LCMS (Method I, ESI): RT=2.53 min, m+H=506.4; 1H NMR (400 MHz, CDCl3) δ: 9.09 (s, 1H), 8.98 (d, 1H), 8.19 (dd, 2H), 7.61 (m, 2H), 7.54-7.49 (m, 2H), 7.35 (br s, 4H), 7.17 (m, 1H), 6.67 (s, 1H), 4.18 (br s, 1H), 3.94 (br s, 1H), 3.18 (br s, 1H), 2.97 (br s, 1H), 2.36 (s, 1H), 2.21-1.98 (m, 5H), 1.41-1.20 (m, 3H). Analysis for racemic trans: LCMS (Method I, ESI): RT=2.56 min, m+H=506.4; 1H NMR (400 MHz, DMSO) δ: 9.07 (d, 1H), 8.92 (s, 1H), 8.15-8.10 (m, 2H), 7.80 (m, 2H), 7.66 (t, 2H), 7.38-7.19 (m, 4H), 7.02 (d, 1H), 4.42 (s, 1H), 3.89 (d, 1H), 2.80-2.57 (m, 2H), 2.34-2.24 (m, 1H), 1.93-1.58 (m, 4H), 1.15 (d, 3H).
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH:5]2[CH2:15][CH2:16][N:2]1[CH2:3][CH2:4]2.Br[C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>>[CH3:30][N:27]1[CH2:28][CH2:29][N:24]([C:21]2[CH:20]=[CH:19][C:18]([N:7]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[C:14]4[CH2:1][N:2]5[CH2:3][CH2:4][CH:5]([C:6]3=4)[CH2:15][CH2:16]5)=[CH:23][CH:22]=2)[CH2:25][CH2:26]1
Reactant: c1ccc2c3c([nH]c2c1)C1CCN(CC1)C3
Reactant: CN1CCN(c2ccc(Br)cc2)CC1
Product: CN1CCN(c2ccc(-n3c4c(c5ccccc53)CN3CCC4CC3)cc2)CC1

Procedure:
The reaction of 3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (212 mg, 1.0 mmol; Example 187A) and 1-(4-bromophenyl)-4-methylpiperazine (255 mg, 1.0 mmol; Accela Chembio) was performed as described in Example 68 to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.92-2.11 (m, 4H) 2.37 (s, 3H) 2.61-2.71 (m, 4H) 2.86-2.92 (m, 1H) 3.03-3.28 (m, 8H) 4.31 (s, 2H) 6.95-7.06 (m, 3H) 7.10-7.21 (m, 4H) 7.32-7.40 (m, 1H); MS (DCI/NH3) m/z 387 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl[CH2:9][N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:11]1(=[O:20])[N:10]([CH2:9][O:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]12
Reactant: Oc1ccncc1
Reactant: O=C1c2ccccc2C(=O)N1CCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1COc1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
To a solution of 4.76 g (50 mmol) of 4-hydroxypyridine and 10.76 g (55 mmol) of N-chloromethylphthalimide in 80 ml of DMF, 8.23 ml (55 mmol) of 1,8-diazabicyclo[5,4,0]-7-undecene was added. The mixture was stirred at room temperature for 2 hours. After the solvent was distilled off, the reaction mixture was poured into water and extracted with ethyl acetate. The precipitate was filtered off. The aqueous layer was further extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 2.67 g of the desired compound (yield: 21%, colorless crystals).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@H:10]([OH:26])[C:11]([N:13]1[CH2:24][C@@H:23]([Cl:25])[CH2:22][C@H:14]1[C:15]([NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:12].N#N.[C:36]([O:40][C:41]([NH:43][C@H:44]([C:49](O)=[O:50])[CH2:45][C:46](=[O:48])[NH2:47])=[O:42])([CH3:39])([CH3:38])[CH3:37]>CN(C)C=O>[C:36]([O:40][C:41]([NH:43][C@H:44]([C:49]([NH:8][C@@H:9]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@H:10]([OH:26])[C:11]([N:13]1[CH2:24][C@@H:23]([Cl:25])[CH2:22][C@H:14]1[C:15]([NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:12])=[O:50])[CH2:45][C:46](=[O:48])[NH2:47])=[O:42])([CH3:38])([CH3:39])[CH3:37]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)O
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)[C@@H](O)[C@@H](N)Cc1ccccc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C
Reaction time: 72 h

Procedure:
4.4 ml (31.4 mmol) of triethylamine were added, whilst ice-cooling, to a solution of 6.0 g (15.7 mmol) of (4S)-1-[(2S,3S)-3-amino-2-hydroxy-4-phenylbutyryl]-4-chloro-N-t-butyl-L-prolinamide [prepared as described in Preparation 21(b)] and 10.6 g (30.0 mmol) of the p-nitrophenyl ester of N2 -t-butoxycarbonyl-L-asparagine in 50 ml of dimethylformamide, and the resulting mixture was stirred for 3 days. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure, and the residue was diluted with methylene chloride. The diluted solution was washed with a 5% w/v aqueous solution of citric acid, with a 1N aqueous solution of sodium hydroxide and with a saturated aqueous solution of sodium chloride, in that order, after which it was concentrated by evaporation under reduced pressure. The residue thus obtained was purified by column chromatography, using a 1:30 by volume mixture of methanol and methylene chloride as the eluent, to give 7.6 g of the title compound as a colorless powder, melting at 126°-132° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5](O)=[O:6].CN(C=O)C.C(Cl)(=O)C([Cl:20])=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([Cl:20])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(F)cc(Br)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 1.67 h

Procedure:
10 g of 3-bromo-5-fluoro-benzoic acid are suspended in 100 ml of DCM, 0.5 ml DMF and 4.5 ml oxalyl chloride (1.15 Eq) are added and the resulting mixture is stirred for 100 minutes at RT. The solvent is removed by vacuo and the benzoic acid chloride is isolated by distillation.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH2:18])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH:24]=O>C(O)(C)C.Cl.C(Cl)(Cl)Cl>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([N:18]=[CH:24][C:20]2[O:19][CH:23]=[CH:22][CH:21]=2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: O=Cc1ccco1
Reactant: CCOCc1nc2cnc3ccccc3c2n1N
Agent: Cl
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2cnc3ccccc3c2n1N=Cc1ccco1
Reaction time: 48 h
Yield: 93.8 %

Procedure:
A solution of 2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-amine (1.50 g, 6.19 mmol) in 20 mL of isopropanol was treated with 2-furaldehyde (1.08 mL, 13.0 mmol) and 2 drops of concentrated HCl and heated to reflux under an atmosphere of nitrogen. After 48 h, the reaction was concentrated under reduced pressure to yield a brown oil. The oil was dissolved in 30 mL of CHCl3 and washed with 5% Na2CO3 solution, water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)(furan-2-ylmethylene)amine (1.86 g) as a light brown solid.
Reaction SMILES: [H-].[Na+].C(NC(C)C)(C)C.[C:10]1([O:20][CH2:21][C:22]([OH:24])=[O:23])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.C([Li])CCC.CCCCCC.[C:36]1([CH2:42][CH2:43][CH2:44][CH2:45]Br)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O1CCCC1>[C:10]1([O:20][CH:21]([CH2:45][CH2:44][CH2:43][CH2:42][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:22]([OH:24])=[O:23])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)COc1cccc2ccccc12
Reactant: BrCCCCc1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: O=C(O)C(CCCCc1ccccc1)Oc1cccc2ccccc12
Temperature: 50 °C
Yield: 23.6 %

Procedure:
To a mixture of 5 ml of dry tetrahydrofuran and 0.26 g of 50% sodium hydride (suspension in oil) were added 0.7 ml of diisopropylamine and 1.0 g of 1-naphthoxyacetic acid with stirring under an argon atmosphere under ice-cooling. The mixture was heated for 30 minutes at 50° C., and then heated under reflux for 15 minutes. After cooling below 5° C., to the reaction mixture was added dropwise 3.5 ml of n-butyllithium (as a 1.6 mole hexane solution), the mixture was stirred below 10° C. for 20 minutes, and then warmed for 20 minutes at 30° C. After cooling below 5° C. again, 1.00 g of 4-phenylbutyl bromide was added to the reaction mixture. The mixture was stirred for 30 minutes at below 5° C., and then warmed for 1 hour at 30° C. with stirring. After cooling, the reaction mixture was washed with diethyl ether to remove neutral materials. The aqueous layer was acidified by adding concentrated hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: benzene) to obtain 0.37 g of (±)-2-(1-naphthoxy)-6-phenylhexanoic acid as colorless crystals.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11](=[S:14])[NH:12][N:13]=2)=[C:5]([O:15][CH3:16])[CH:4]=1)[CH3:2].Br.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>CCO.CCOC(C)=O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][N:12]=[C:11]([S:14][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[N:10]=2)=[C:5]([O:15][CH3:16])[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(-c2n[nH]c(=S)[nH]2)c(OC)c1
Reactant: BrCc1ccccn1
Agent: Br
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCc1ccc(-c2nc(SCc3ccccn3)n[nH]2)c(OC)c1
Temperature: 60 °C
Yield: 67.7 %

Procedure:
To a solution of 5-(4-ethyl-2-methoxyphenyl)-2H-1,2,4-triazole-3(4H)-thione (example 18a) (100 mg, 0.43 mmol) in EtOH (2 mL) was added 2-(bromomethyl)pyridine hydrobromide (129 mg, 0.51 mmol). The suspension was heated at 60° C. for 22 h. The reaction mixture was diluted with EtOAc and washed successively with water and brine, dried over MgSO4, filtered and evaporated. The residue was purified on silica gel (Eluent: 5% MeOH in DCM) to give 2-((5-(4-ethyl-2-methoxyphenyl)-1H-1,2,4-triazol-3-ylthio)methyl)pyridine (95 mg) as a white powder (68%). 1H NMR (300 MHz, dMSO): δ 1.19-1.22 (t, 3H), 2.63-2.69 (dd, 2H), 3.93 (s, 3H), 4.48 (s, 2H), 6.93-7.03 (m, 2H), 7.25-7.29 (m, 1H), 7.49-7.5 (m, 1H), 7.71-7.75 (m, 1H), 7.93-7.95 (d, 1H), 8.50-8,51 (d, 1H), 13.65 (bs, 1H), MS (M+H, 327).