Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]1[CH2:13][N:14]([CH2:17][C:18]([NH:20][CH:21]([CH:28]([CH3:30])[CH3:29])[CH:22]([OH:27])[C:23]([F:26])([F:25])[F:24])=[O:19])[CH:15]=[CH:16][C:9]2=1)([OH:3])=O.C(OC(C1C=CC=C2C=1[NH:43]C1CN(CC(NC(C(C)C)C(O)C(F)(F)F)=O)C=CC2=1)=O)C>>[C:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]1[CH2:13][N:14]([CH2:17][C:18]([NH:20][CH:21]([CH:28]([CH3:29])[CH3:30])[C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])=[O:19])[CH:15]=[CH:16][C:9]2=1)(=[O:3])[NH2:43]
Reactant: CCOC(=O)c1cccc2c3c([nH]c12)CN(CC(=O)NC(C(C)C)C(O)C(F)(F)F)C=C3
Reactant: CC(C)C(NC(=O)CN1C=Cc2c([nH]c3c(C(=O)O)cccc23)C1)C(O)C(F)(F)F
Product: CC(C)C(NC(=O)CN1C=Cc2c([nH]c3c(C(N)=O)cccc23)C1)C(=O)C(F)(F)F

Procedure:
2-(8-Carboxy-1,2-dihydropyrido[3,4-b]indol-2-yl)-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)acetamide. 2-(8-Ethoxycarbonyl-1,2-dihydropyrido[3,4-b]indol-2-yl)-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)acetamide was subjected to a hydrolysis procedure similar to that outlined in Example 3 to give the title compound as a white solid;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[CH2:16](O)[CH3:17]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:16][CH3:17])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: O=C(O)Cc1cccc(Br)c1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cc1cccc(Br)c1
Temperature: 0 °C

Procedure:
Commercially available 2-(3-bromophenyl)acetic acid (13 g 0.06 mol) was dissolved in ethanol (130 ml) and cooled to 0° C. Thionyl chloride (20 ml) was added drop wise. The mixture was heated to 85° C. over night. Reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The organic layer was washed with 10% NaHCO3, water, dried over anhydrous sodium sulfate and concentrated to give 13 g (88%) of A6.1a.
Reaction SMILES: FC1C=CC=CC=1C(Cl)=O.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17].[NH2:24][C:25]1[CH:26]=[C:27]([CH:38]=[CH:39][N:40]=1)[C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>>[CH2:31]([NH:30][C:28](=[O:29])[C:27]1[CH:38]=[CH:39][N:40]=[C:25]([NH:24][C:16](=[O:17])[C:15]2[CH:19]=[CH:20][CH:21]=[C:13]([C:12]([F:23])([F:22])[F:11])[CH:14]=2)[CH:26]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccn1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: O=C(Cl)c1ccccc1F
Product: O=C(NCc1ccccc1)c1ccnc(NC(=O)c2cccc(C(F)(F)F)c2)c1
Yield: 80 %

Procedure:
Following the procedure as describe in Example 6, making non-critical variations as required to replace 2-fluorobenzoyl chloride with 3-(trifluoromethyl)benzoyl chloride to react with 2-amino-N-benzylisonicotinamide, N-benzyl-2-(3-(trifluoromethyl)benzamido)-isonicotinamide was obtained as a colorless solid in 80% yield: mp 126-128° C.; 1H NMR (300 MHz, CDCl3) δ 10.36 (s, 1H), 8.82 (s, 1H), 8.41-8.14 (m, 4H), 7.95-7.27 (m, 7H), 7.03 (s, 1H), 4.57 (d, J=5.1 Hz, 2H); MS (ES+) m/z 400.5 (M+1).
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[N:7]=1.[NH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.CC(C)([O-])C.[Na+]>C1COCC1>[Br:8][C:6]1[N:7]=[C:2]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1
Reactant: Nc1cccnc1
Reactant: Cn1cc(Br)nc(Br)c1=O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc(Br)nc(Nc2cccnc2)c1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 35.3 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was charged with THF (15 mL), 3,5-dibromo-1-methylpyrazin-2(1H)-one (1.00 g, 3.73 mmol), 3-aminopyridine (351 mg, 3.73 mmol) and sodium tert-butoxide (789 mg, 8.21 mmol). After bubbling nitrogen through the resulting solution for 30 min, di-1-bromobis(tri-t-butylphosphino)dipalladium(I) (29 mg, 0.037 mmol) was added, and the reaction mixture was stirred at room temperature for 2.5 h. After this time the reaction was partitioned between ethyl acetate (50 mL) and water (50 mL) and filtered. The aqueous layer was separated and extracted with ethyl acetate (2×25 mL). The organic layers were combined, washed with brine (50 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford a 35% yield (370 mg) of 111b as a brown solid: mp>250° C.; 1H NMR (500 MHz, DMSO-d6) d 9.75 (s, 1H), 9.08 (d, 1H, J=2.5 Hz), 8.32 (m, 1H), 8.24 (dd, 1H, J=5.0, 1.5 Hz), 7.40 (s, 1H), 7.36 (dd, 1H, J=8.5, 4.5 Hz), 3.45 (s, 3H); MS (APCI+) m/z 281.0 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([OH:14])([CH3:13])[CH3:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1B(O)O.C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].C(NC(C)C)(C)C>CN(C)C=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C:2]1[CH:10]=[C:9]([C:11]([OH:14])([CH3:13])[CH3:12])[CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: CC(C)(O)c1cc(Br)cc(C(=O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CC(C)(O)c1cc(C(=O)O)cc(-c2ccc(F)cc2F)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
To a solution of 3-bromo-5-(1-hydroxy-1-methylethyl)benzoic acid (150 mg, 0.579 mmol) in N,N-dimethylformamide (2.90 mL) and water (0.97 mL) was added (2,4-difluorophenyl)boronic acid (110 mg, 0.695 mmol), palladium(II) acetate (6.5 mg, 0.029 mmol), 3,3′3″-phosphinidynetris(benzenesulfonic acid)trisodium salt (49.4 mg, 0.087 mmol) and diisopropylamine (0.206 mL, 1.45 mmol) and the mixture was heated to 80° C. After 3 h, filtration and purification by reverse phase chromatography (C-18, 90% water/acetonitrile→30% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (156 mg).
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[C:17](I)=[C:16]([CH2:19][CH3:20])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C=C.[C:23]([O-])(=O)[CH3:24].[K+]>CO.[Pd]>[C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[C:17]([CH:23]=[CH2:24])=[C:16]([CH2:19][CH3:20])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CCc1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1I
Agent: [Pd]
Agent: C=C
Agent: [K+]
Solvent: CO
Product: C=Cc1c(CC)ncnc1N[C@H]1CC[C@@H](C(C)(C)C)CC1
Reaction time: 24 h

Procedure:
3.9 g (10 mmol) of 4-(cis-4-tert-butylcyclohexylamino)-6-ethyl-5-iodopyrimidine (Example 1) were treated with 10 bar of ethylene in an autoclave at 120° C. in the presence of 1.5 g (15 mmol) of potassium acetate and 50 mg of palladium black in 100 ml of methanol. After 24 hours, the catalyst was removed by filtration and the mixture was concentrated. Chromatography on silica gel gave 1.70 g (61.8% of theory) of colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C@H:13]([OH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:10][C@H:9]1[CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:31]1([CH:34]2[CH2:38][C:37]3([CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)[C:36](=[O:44])[O:35]2)[CH2:33][CH2:32]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[CH:31]1([CH:34]2[CH2:38][C:37]3([CH2:43][CH2:42][N:41]([C:26]([C:25]4[CH:29]=[CH:30][C:22]([CH2:21][C@@H:9]5[CH2:10][CH2:11][C@H:12]([C@H:13]([OH:20])[C:14]6[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=6)[N:8]5[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:23][CH:24]=4)=[O:27])[CH2:40][CH2:39]3)[C:36](=[O:44])[O:35]2)[CH2:33][CH2:32]1
Reactant: O=C1OC(C2CC2)CC12CCNCC2
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)O)cc2)CC[C@@H]1[C@H](O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)N3CCC4(CC3)CC(C3CC3)OC4=O)cc2)CC[C@@H]1[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.8 %

Procedure:
To a solution of 0.16 g (0.39 mmol) of 4-({(2S,5R)-1-(tert-butoxycarbonyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)benzoic acid (i-1) in 2 ml anhydrous DMF at ambient temperature was added 0.14 g (0.58 mmol) 3-cyclopropyl-2-oxa-8-azaspiro[4.5]decan-1-one from the above, followed by 0.12 g (0.58 mmol) EDCl, 0.08 g (0.58 mmol) HOBt, and 0.34 ml (1.94 mmol) N,N-diisopropylethylamine. The solution was stirred for 2 h at ambient temperature. The solution was poured into water (20 ml) and extracted with ethyl acetate (2×20 ml). The combined organic layers were extracted with brine (20 ml). It was dried over magnesium sulfate and concentrated. The residue was purified using a Biotage Horizon® system (50-100% ethyl acetate/hexanes mixture) to give 0.135 g of the title compounds as a mixture of diastereomers in a 50:50 ratio. The two diastereomers were separated by chiral HPLC employing a Daicel CHIRALPAK® OD® column (eluent: 40% IPA in Heptane). The first eluting diastereomer was designated as Isomer 1 and is colorless solid (0.030 g, 16%). LC/MS 589.3 (M+1). The second eluting diastereomer was designated as Isomer 2 and is a colorless solid (0.025 g, 13%). LC/MS 589.3 (M+1).
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([CH:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH2:33][CH2:34][C:35]5[N:36]([C:38]([C:41]([F:44])([F:43])[F:42])=[N:39][N:40]=5)[N:37]=4)[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[C:45](O)(=[O:47])[CH3:46].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:45]([N:13]1[CH2:12][CH2:11][N:10]([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]([CH:26]3[CH2:27][CH2:28][N:29]([C:32]4[CH2:33][CH2:34][C:35]5[N:36]([C:38]([C:41]([F:44])([F:43])[F:42])=[N:39][N:40]=5)[N:37]=4)[CH2:30][CH2:31]3)=[CH:24][CH:25]=2)[CH2:15][CH2:14]1)(=[O:47])[CH3:46]
Reactant: FC(F)(F)c1nnc2n1N=C(N1CCC(c3ccc(OCCCN4CCNCC4)cc3)CC1)CC2
Reactant: CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN(CCCOc2ccc(C3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.3 %

Procedure:
DIPEA (0.159 mL, 0.92 mmol) was added to 6-[4-[4-[3-(piperazin-1-yl)propoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazine (150 mg, 0.31 mmol), acetic acid (0.021 mL, 0.37 mmol) and HATU (139 mg, 0.37 mmol) in DMF (2 mL). The resulting solution was stirred at ambient temperature for 16 hours then purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to give 6-[4-[4-[3-(4-acetylpiperazin-1-yl)propoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (75 mg, 46.1%) as a solid.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[CH:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)=[CH2:31].Br[C:39]1[CH:40]=[CH:41][C:42]2[C:43]3[N:52]([CH2:53][CH2:54][CH2:55][O:56][CH3:57])[C:51]([CH2:58][O:59][CH2:60][CH3:61])=[N:50][C:44]=3[C:45]([NH2:49])=[N:46][C:47]=2[CH:48]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH2:60]([O:59][CH2:58][C:51]1[N:52]([CH2:53][CH2:54][CH2:55][O:56][CH3:57])[C:43]2[C:42]3[CH:41]=[CH:40][C:39](/[CH:31]=[CH:30]/[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)=[CH:48][C:47]=3[N:46]=[C:45]([NH2:49])[C:44]=2[N:50]=1)[CH3:61]
Reactant: C=Cc1ccccn1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCOC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc3cc(/C=C/c4ccccn4)ccc3c2n1CCCOC
Temperature: 120 °C

Procedure:
A thick walled glass tube, equipped with magnetic stir-bar, was charged with toluene (20 mL/g), palladium (II) acetate (0.1 equivalents), tri-ortho-tolylphosphine (0.3 equivalents), triethylamine (3.0 equivalents), 2-vinylpyridine (1.0 equivalent), and 7-bromo-2-ethoxymethyl-1-(3-methoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.0 eq.). The tube was purged with nitrogen and sealed. The reaction mixture was heated at 120° C. for 24-48 hours. The reaction mixture was allowed to cool and then concentrated under reduced pressure. The solid residue was partitioned between dichloromethane and water, and the mixture was adjusted to pH 12 with the addition of 10% aqueous sodium hydroxide. The organic layer was separated and purified by flash chromatography on silica gel (eluting with chloroform:methanol in a gradient from 100:0 to 90:10) followed by recrystallization from acetonitrile to provide (E)-2-ethoxymethyl-1-(3-methoxypropyl)-7-(2-pyridin-2-ylvinyl)-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(N(CC)CC)C>O1CCOCC1>[NH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][S:17]([C:14]1[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:16][CH:15]=1)(=[O:19])=[O:18]
Reactant: Nc1ccccc1N
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccc(S(=O)(=O)Nc2ccccc2N)cc1
Yield: 97.4 %

Procedure:
33.1 g (0.3 mol) of 1,2-phenylenediamine was dissolved in 200 ml of dioxane. A solution of 20.87 g (0.1 mol) of 4-methoxybenzenesulfonyl chloride in 110 ml of dioxane was added thereto under stirring. The resulting mixture was stirred at room temperature overnight. 12.1 g (0.12 mol) of triethylamine was added thereto. After concentration followed by addition of an aqueous citric acid solution and ethyl acetate, the organic layer was separated, concentrated and purified by silica gel column chromatography to obtain 27.1 g of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[C:9](=[O:15])[N:8]([CH:16]1[CH2:21][CH2:20][N:19]([C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]1)[C:7]2=[O:36])(=[O:3])C.Br[OH:38].BrBr.[OH-].[Na+].Cl>O1CCOCC1.C(Cl)(Cl)Cl>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[C:9](=[O:15])[N:8]([CH:16]1[CH2:17][CH2:18][N:19]([C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH2:20][CH2:21]1)[C:7]2=[O:36])([OH:3])=[O:38]
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)c5cc(C(C)=O)ccc5n(C)c4=O)CC3)c2cc1OC
Reactant: OBr
Agent: BrBr
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(N3CCC(n4c(=O)c5cc(C(=O)O)ccc5n(C)c4=O)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 21.3 %

Procedure:
In a solvent mixture of 30 ml of 1,4-dioxane and 5 ml of chloroform was suspended 245.0 mg (0.50 mmol) of Compound 63 obtained in Example 50. The suspension was added to a solution of hypobromous acid (3 mmol) which was prepared by adding 0.15 ml of bromine to a solvent mixture of 3 ml of a 2N aqueous solution of sodium hydroxide and 1 ml of 1,4dioxane under ice cooling. The mixture was stirred at room temperature for one day, and then neutralized by addition of 4N hydrochloric acid, followed by extraction with chloroform. The organic layer was washed and dried, and the solvent was distilled off under reduced pressure. To the residue was added ether, and the precipitated crystals were collected by filtration and dried to give 52.4 mg (yield: 21%) of Compound 62 as white crystals.
Reaction SMILES: C([O:8][C:9]1[C:27]([O:28][CH3:29])=[CH:26][C:12]([C:13]([N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[S:17](=[O:25])(=[O:24])[CH2:16]2)=[O:14])=[CH:11][C:10]=1[Cl:30])C1C=CC=CC=1>O1CCCC1.[OH-].[Pd+2].[OH-].[C]>[Cl:30][C:10]1[CH:11]=[C:12]([CH:26]=[C:27]([O:28][CH3:29])[C:9]=1[OH:8])[C:13]([N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[S:17](=[O:24])(=[O:25])[CH2:16]1)=[O:14]
Reactant: COc1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(Cl)c1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(Cl)c1O
Temperature: 25 °C
Reaction time: 21 h
Yield: 44.7 %

Procedure:
3-(4-benzyloxy-3-chloro-5-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (519 mg) was dissolved in tetrahydrofuran (5 mL), and 20% palladium hydroxide-carbon (101 mg) was added to the solution, and then the mixture was stirred at room temperature for 21 hours under a hydrogen atmosphere. After the reaction solution was filtered, the solvent was distilled off under reduced pressure and then the obtained residue was crystallized from chloroform to obtain the title compound (185 mg) as a colorless crystal.
Reaction SMILES: [C:1]([C:3]1([NH:23][C:24](=[O:26])[CH3:25])[CH2:8][CH2:7][CH:6]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16](OCC)=[C:15](C)[CH:14]=2)(=[O:12])=[O:11])[CH2:5][CH2:4]1)#[N:2].NC1(C#N)CCC(NS(C2C=CC([C:44]([F:47])([F:46])[F:45])=CC=2)(=O)=O)CC1>>[C:1]([C:3]1([NH:23][C:24](=[O:26])[CH3:25])[CH2:4][CH2:5][CH:6]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([C:44]([F:47])([F:46])[F:45])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:7][CH2:8]1)#[N:2]
Reactant: CCOc1ccc(S(=O)(=O)NC2CCC(C#N)(NC(C)=O)CC2)cc1C
Reactant: N#CC1(N)CCC(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Product: CC(=O)NC1(C#N)CCC(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1

Procedure:
Intermediate 127 was prepared by a method analogous to the method of preparing Intermediate 126 using N-(4-amino-4-cyanocyclohexyl)-4-trifluoromethyl benzenesulfonamide (Intermediate 125) as the starting material.
Reaction SMILES: FC1C=CC(O)=CC=1.BrCCCCCCCCCO.[F:20][C:21]1[CH:37]=[CH:36][C:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35])=[CH:23][CH:22]=1.FC1C=CC(OCCCCCCCCC(O)=O)=CC=1.Cl.Cl.[CH2:59]([O:66][C:67](=[O:75])[CH2:68][C@@H:69]([NH2:74])[CH2:70][N:71]([CH3:73])[CH3:72])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>>[CH2:59]([O:66][C:67](=[O:75])[CH2:68][C@@H:69]([NH:74][C:34](=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][O:25][C:24]1[CH:36]=[CH:37][C:21]([F:20])=[CH:22][CH:23]=1)[CH2:70][N:71]([CH3:72])[CH3:73])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: OCCCCCCCCCOc1ccc(F)cc1
Agent: Cl
Agent: O=C(O)CCCCCCCCOc1ccc(F)cc1
Agent: OCCCCCCCCCBr
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCCOc1ccc(F)cc1

Procedure:
The title compound, m/e=395.5 ([M−H]−), was produced in analogy with example 18, steps 1 to 4. Thus, 4-fluorophenol was alkylated in step 1 with 9-bromo-1-nonanol, leading to 9-(4-fluoro-phenoxy)-nonan-1-ol, which was oxidized in step 2 to 9-(4-fluoro-phenoxy)-nonanoic acid. This was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-4-dimethylamino-3-[9-(4-fluoro-phenoxy)-nonanoylamino]-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C@@H:13]([OH:30])[C@@H:14]([N+:27]([O-])=O)[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=2)[CH2:11][O:10][C:9]1([CH3:32])[CH3:31])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.[Zn]>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C@@H:13]([OH:30])[C@@H:14]([NH2:27])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:24])([F:25])[F:26])[CH:17]=2)[CH2:11][O:10][C:9]1([CH3:32])[CH3:31])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H]([C@@H](O)[C@H](Cc2cccc(OC(F)(F)F)c2)[N+](=O)[O-])COC1(C)C
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1[C@@H]([C@@H](O)[C@@H](N)Cc2cccc(OC(F)(F)F)c2)COC1(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.4 %

Procedure:
Add zinc (8.46 g, 129.4 mmoles) to (R)-4-[(1R,2S)-1-Hydroxy-2-nitro-3-(3-trifluoromethoxy-phenyl)-propyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (6.01 g, 12.9 mmoles) in acetic acid (75 mL) and stir at room temperature for 10 minutes. Filter and wash the solids with water. Extract with ethyl acetate. Wash organic layer with 0.1 N sodium hydroxide and saturated aqueous sodium chloride. Dry over sodium sulfate, filter and concentrate to give 5.18 g (92% yield) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:11].[N-:12]=[N+:13]=[N-:14].[Na+].[Cl-].C([NH+](CC)CC)C.Cl>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([C:6]2[N:12]=[N:13][NH:14][N:7]=2)=[CH:8][C:9]=1[CH3:10]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(C#N)cc(C)c1Br
Agent: CC[NH+](CC)CC
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1C
Product: Cc1cc(-c2nn[nH]n2)cc(C)c1Br
Temperature: 115 °C
Reaction time: 8 h

Procedure:
5-(4-Bromo-3,5-dimethylphenyl)-2H-tetrazole may be obtained as follows: To a solution of 135 g (0.642 mol) 4-bromo-3,5-dimethylbenzonitrile in 960 mL anhydrous xylene, 141.6 g (1.028 mol) sodium azide and 10.48 g (1.028 mol) triethylammonium chloride is added. The mixture is heated to 115° C. and stirred overnight. After cooling to r.t. the reaction mixture is poured into 2 L of ice water and the pH is adjusted to pH=1 by acidification with conc. aq. hydrochloric acid. Stirring is continued for 1 h. The crude product is filtered off, washed with n-hexane (lx 500 mL) and water (3×600 mL) and dried to yield the intermediate 5-(4-bromo-3,5-dimethylphenyl)-2H-tetrazole. 166 g (0.29 mol) 5-(4-bromo-3,5-dimethylphenyl)-2H-tetrazole is dissolved in 3.2 L DMF and cooled to −10° C., before 305 g (2.15 mol) iodomethane is added. Afterwards, a solution of 71.3 g (0.742 mol) sodium tert-butoxide in 810 mL anhydrous THF is added slowly over a period of 25 min whilst keeping the temperature constant. After full conversion the reaction mixture is warmed to r.t. and poured into 1 L water. The resulting suspension is stirred for an additional hour at r.t. The crude product is filtered off, washed with water (3×1 L) and dried. After recrystallization from acetonitrile/water (1:1) mixture 90.8 g of the title compound is obtained as off white solid.
Reaction SMILES: C(OC([N:6]1[CH2:21][CH2:20][CH:19]([O:22]C(OCC)=O)[C:9]2=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]([CH3:18])=[C:8]2[CH2:7]1)=O)C.[ClH:28]>>[ClH:28].[ClH:28].[OH:22][CH:19]1[C:9]2=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]([CH3:18])=[C:8]2[CH2:7][NH:6][CH2:21][CH2:20]1
Reactant: CCOC(=O)OC1CCN(C(=O)OCC)Cc2c1nc1ccccc1c2C
Agent: Cl
Product: Cc1c2c(nc3ccccc13)C(O)CCNC2
Yield: 70 %

Procedure:
2,3,4,5-Tetrahydro-5-hydroxy-11-methyl-1H-azepino[4,3-b]quinoline dihydrochloride was prepared from 5-(ethoxy-carbonyloxy)-2,3,4,5-tetrahydro-11-methyl-1H-2-azepino[4,3-b]quinoline-carboxylic acid ethyl ester by hydrolysis with 2 N hydrochloric acid.