Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6](=O)[CH3:7].[CH:13]([O:16][C:17](=[O:22])[CH2:18][C:19](=[NH:21])[NH2:20])([CH3:15])[CH3:14]>C(O)(C)C>[CH:13]([O:16][C:17]([C:18]1[CH:4]([C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=2[Cl:1])[CH:5]=[C:6]([CH3:7])[NH:21][C:19]=1[NH2:20])=[O:22])([CH3:15])[CH3:14]
Reactant: CC(=O)C=Cc1ccccc1Cl
Reactant: CC(C)OC(=O)CC(=N)N
Solvent: CC(C)O
Product: CC1=CC(c2ccccc2Cl)C(C(=O)OC(C)C)=C(N)N1
Yield: 51 %

Procedure:
Upon heating a solution of 18.1 g of 2-chlorobenzylideneacetone and 14.1 g of amidinoacetic acid isopropyl ester in 200 ml of isopropanol for 3 hours, 2-amino-6-methyl4-(2-chlorophenyl)-1,4-dihydropyridine-3-carboxylic acid isopropyl ester of melting point 161°C (isopropanol) is obtained. Yield: 51 percent of theory.
Reaction SMILES: O([C:8]([NH:10][C:11]1[CH:34]=[CH:33][CH:32]=[CH:31][C:12]=1[C:13]([NH:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:23])[CH2:18][CH2:17]1)=[O:14])=[O:9])C1C=CC=CC=1.[CH2:35]([NH2:42])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>C1(C)C=CC=CC=1>[CH2:35]([NH:42][C:8](=[O:9])[NH:10][C:11]1[CH:34]=[CH:33][CH:32]=[CH:31][C:12]=1[C:13]([NH:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:23])[CH2:18][CH2:17]1)=[O:14])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: O=C(Nc1ccccc1C(=O)NC1CCN(C(=O)Oc2ccccc2)CC1)Oc1ccccc1
Reactant: CCCCCCCN
Solvent: Cc1ccccc1
Product: CCCCCCCNC(=O)Nc1ccccc1C(=O)NC1CCN(C(=O)Oc2ccccc2)CC1
Yield: 95 %

Procedure:
A solution of 2-phenoxycarbonylamino-N-(1-phenoxylcarbonylpiperidin-4-yl)benzamide (1.6 g, 3.5 mmol) and n-heptylamine (0.45 g, 3.9 mmol) in toluene (20 ml) was refluxed for 4 hours and then concentrated. The residue was purified by column chromatography on silica gel (50% ethyl acetate in petroleum ether) to give 2-(N'-n-heptylureido)-N-(1-phenoxy carbonylpiperidin-4-yl)benzamide: yield 95.0%: mp 142°-144° C.; 1H NMR (CDCl3)ppm: 0.88 (3H, t) 1.28-1.33 (7H, m), 19-1.62 (4H, m), 2.05-2.17 (2H, m), 3.04-3.19 (2H, m), 3.25 (2H, q), 4.10-4.15 (1H, m), 4.24-4.40 (2H, m), 4.59 (1H, t), 6.35 (1H, d), 6.92 (1H, t), 6.97-7.44 (8H, m), 8.40 (1H,d), 10.20 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[OH:13][C@:14]([CH3:50])([CH2:48][OH:49])[C:15](=[O:47])[C@@H:16]([NH:24][C:25](=[O:46])[C@@H:26]([NH:30][C:31](=[O:45])[C@@H:32]([NH:36][C:37]([C:39]1[S:43][C:42]([CH3:44])=[N:41][CH:40]=1)=[O:38])[CH2:33][O:34][CH3:35])[CH2:27][O:28][CH3:29])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[F:1][C:2]1[CH:3]=[C:4]([S:9]([O:49][CH2:48][C@:14]([OH:13])([CH3:50])[C:15](=[O:47])[C@@H:16]([NH:24][C:25](=[O:46])[C@@H:26]([NH:30][C:31](=[O:45])[C@@H:32]([NH:36][C:37]([C:39]2[S:43][C:42]([CH3:44])=[N:41][CH:40]=2)=[O:38])[CH2:33][O:34][CH3:35])[CH2:27][O:28][CH3:29])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:10])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)CO
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Product: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)COS(=O)(=O)c1ccc(F)c(F)c1

Procedure:
Prepared according to procedures described above, by reacting 3,4-difluorobenzenesulfonyl chloride with N—((S)-1-(((S)-1-(((2S,4R)-4,5-dihydroxy-4-methyl-3-oxo-1-phenylpentan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-2-methylthiazole-5-carboxamide. MS for C31H36F2N4O10S2 m/z: 727 (M+H)+.
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:4]=[CH:3]1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>[OH-].[Na+].O>[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17]([N:2]2[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:4]=[CH:3]2)(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)Cc1c[nH]cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cnc(CC(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
To a solution of 4-imidazole acetic acid hydrochloride (1 g, 6.15 mmol) in 6.2 mL of 1 N NaOH and 18 mL of water was added 4-toluenesulfonyl chloride (1.29 g, 6.77 mmol) and the mixture was stirred at ambient temperature. The pH of the mixture was maintained at 8.5 by addition of 1 N NaOH. After 3 hours, a total volume of 12 mL of 1 N NaOH was added and a clear solution was obtained. This solution was extracted with ether and the aqueous solution was acidified to pH 1 with 3 N HCl. The mixture was cooled in an ice bath and N-(4-Toluenesulfonyl)imidazole-4-yl-acetic acid was isolated by filtration (white crystals, 1.10 g, 63% yield). m.p. 105-106° C. (decomp); 1H NMR (CDCl3) δ 10.0 (br, 1H), 8.04 (s, 1H), 7.82 (d, J=8.2 Hz, 2H), 7.37 (d, J=8.2 Hz, 2H), 7.28 (s, 1H), 3.65 (s, 2H), 2.45 (s, 3H). 13C NMR (CD3OD) δ 173.6, 148.1, 138.9, 138.0, 136.1, 131.6, 128.7, 117.0, 34.0, 21.6.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.[OH-].[NH4+:13]>C1COCC1>[F:9][C:8]([F:11])([F:10])[C:5]1[N:4]=[N:3][C:2]([NH2:13])=[CH:7][CH:6]=1
Reactant: [NH4+]
Reactant: FC(F)(F)c1ccc(Cl)nn1
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1ccc(C(F)(F)F)nn1
Temperature: 100 °C
Yield: 93 %

Procedure:
A mixture of 3-chloro-6-trifluoromethylpyridazine (1.6 g, 8.80 mmol) and ammonium hydroxide (9 mL) in THF (3 mL) was heated at 100° C. in a microwave reactor for 1 h. After this period, the reaction mixture was evaporated and the residue was extracted with dichloromethane. The combined extract was dried over with MgSO4, filtered, and evaporated under reduce pressure to afford 301a (1.3 g, 93%) as a white solid. MS-ESI: [M+H]+ 164.1
Reaction SMILES: Br[CH:2]([CH2:8][CH:9]=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:11]([NH2:16])(=[S:15])[CH2:12][CH2:13][CH3:14].C(=O)(O)[O-].[Na+]>ClC(Cl)C>[CH2:12]([C:11]1[S:15][C:8]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:9][N:16]=1)[CH2:13][CH3:14]
Reactant: CCOC(=O)C(Br)CC=O
Reactant: CCCC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCc1ncc(CC(=O)OCC)s1
Yield: 73.3 %

Procedure:
A mixture of 20.6 g of ethyl 2-bromo-4-oxo-butyrate, 10.9 g of thiobutyramide and 400 ml of dichloroethane was refluxed under a nitrogen atmosphere which recycling the dehydrated condensate. The mixture was cooled and then mixed with 45 ml of a saturated sodium bicarbonate aqueous solution. The mixture was decanted and the organic phase was dried and evaporated to dryness. The liquid residue was chromatographed over silica gel and elution with a 8-2 cyclohexane-benzene mixture yielded 15.4 g of ethyl 2-propyl-5-thiazole-acetate. The IR spectrum in CHCl3 showed an ester carbonyl at 1737cm-1 and C=C at 1536cm-1
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=1)[CH2:16][O:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O.C(O)(=O)[CH2:30][C:31]([OH:33])=[O:32].N1CCCCC1>N1C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=1)[CH2:16][O:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=[CH:30][C:31]([OH:33])=[O:32]
Reactant: O=Cc1ccccc1OCc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1ccccc1OCc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
2-[3-(Quinolin-2-ylmethoxy)-benzyloxy]-benzaldehyde (110 mg, 0.3 mmol, example 56) is dissolved in pyridine (1 mL). Malonic acid (63 mg, 0.6 mmol) and piperidine (10 μL, 0.1 mmol) are added and the contents are heated to 85° C. for 2 hrs, then at 110° C. for another 2 hrs. The reaction is cooled and placed under a nitrogen stream at 40° C. to remove the pyridine. A small amount of toluene is added and the contents are again placed under a nitrogen stream at 40° C. (repeat). The crude material is purified on silica gel by flash chromatography (silica, 2.5% methanol in dichloromethane) to give the title compound. 1H NMR (300 MHz, CDCl3) δ 8.33 (d, 1H), 8.21–8.16 (m, 2H), 7.81–7.70 (m, 3H), 7.56–7.50 (m, 2H), 7.37–7.25 (m, 3H), 7.03–6.93 (m, 4H), 6.50 (d, 1H), 5.48 (s, 2H), 5.14 (s, 2H); MS (ion spray) 412 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1.[NH2:14][CH:15]([CH2:18][CH3:19])[CH2:16]O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:18]([CH:15]1[N:14]2[N:4]=[C:5]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)[CH:6]=[CH:7][C:2]2=[N:3][CH2:16]1)[CH3:19]
Reactant: Clc1ccc(-c2cccnc2)nn1
Reactant: CCC(N)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCC1CN=C2C=CC(c3cccnc3)=NN21
Temperature: 130 °C

Procedure:
A mixture of 5 g of 3-chloro-6-(3-pyridinyl)pyridazine and 30 ml of 2-amino-1-butanol is heated at 130° C. for 18 hours. Then the volatiles are removed by bulb to bulb distillation under high vacuum. As for Example 1, the product is reacted with thionyl chloride and the obtained product is ring closed with potassium carbonate in ethanol to give 2,3-dihydro-3-ethyl-6-(3-pyridinyl)imidazo[1,2-b]pyridazine which is dehydrogenated with lead tetraacetate in dichloromethane to give the desired product 3-ethyl-6-(3-pyridinyl)imidazo[1,2-b]pyridazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:16][CH2:17][OH:18])[CH2:15][CH2:14][NH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[Na+].[Na+].[CH3:25][O:26][C:27]1[CH:35]=[CH:34][C:33]([N:36]2[CH:40]=[N:39][N:38]=[N:37]2)=[CH:32][C:28]=1[C:29](Cl)=[O:30].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O.C(OCC)(=O)C>[CH3:25][O:26][C:27]1[CH:35]=[CH:34][C:33]([N:36]2[CH:40]=[N:39][N:38]=[N:37]2)=[CH:32][C:28]=1[C:29]([N:13]1[CH2:14][CH2:15][C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)([CH2:16][CH2:17][OH:18])[CH2:12]1)=[O:30]
Reactant: COc1ccc(C2(CCO)CCNC2)cc1OC
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(C2(CCO)CCN(C(=O)c3cc(-n4cnnn4)ccc3OC)C2)cc1OC
Temperature: -5 °C
Reaction time: 18 h

Procedure:
Combine 3-(3,4-dimethoxyphenyl)--3-(2-hydroxyethyl)pyrrolidine (5.34 g, 21.2 mmol) and sodium carbonate (1.24 g, 11.7 mmol) in ethyl acetate/water (4/1) (120 mL). Cool the reaction mixture to -5° C. with an salt-ice bath. Slowly, add 2-methoxy-5-(1H-tetrazol-1-yl)benzoyl chloride (22.3 mmol) as a solution in ethyl acetate (60 mL) at a rate such that the temperature of the reaction mixture does not rise above 0° C. Maintain the reaction temperature at about 0° C. After 18 hours, separate the organic layer. Extract the organic layer twice with 1M aqueous hydrochloric acid solution, saturated solution of sodium bicarbonate, water and a saturated solution of sodium chloride. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Combine the aqueous layers and neutralize with a saturated solution of sodium bicarbonate. Extract the neutralized aqueous layers with dichloromethane. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]3[CH2:26][C:25]([CH3:28])([CH3:27])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:29]([OH:31])=O)[CH:23]=4)[NH:18]3)[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:32][S:33]([NH2:36])(=[O:35])=[O:34]>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]3[CH2:26][C:25]([CH3:27])([CH3:28])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:29]([NH:36][S:33]([CH3:32])(=[O:35])=[O:34])=[O:31])[CH:23]=4)[NH:18]3)[CH:12]=2)=[CH:7][CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CS(N)(=O)=O
Reactant: CC(C)(C)c1ccc(-c2cccc(C3CC(C)(C)c4cc(C(=O)O)ccc4N3)c2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(-c2cccc(C3CC(C)(C)c4cc(C(=O)NS(C)(=O)=O)ccc4N3)c2)cc1
Yield: 20 %

Procedure:
A mixture of 2-(4′-tert-butyl-biphenyl-3-yl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.24 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (70 mg, 0.36 mmol), 4-dimethylaminopyridine (44 mg, 0.36 mmol), methane sulfonamide (68.4 mg, 0.72 mmol) in dichloromethane (10 mL) was refluxed for 12 h. Removal of the solvent to afford the oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-[2-(4′-tert-butyl-biphenyl-3-yl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (23.5 mg, 20%) as a light yellow solid: MS (ESI) M+1=491.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[NH:19][C:20](=[O:31])[C:21]1[CH:26]=[CH:25][C:24](F)=[C:23]([N+:28]([O-:30])=[O:29])[CH:22]=1.[CH3:32][NH:33][CH3:34].O>C(#N)C>[CH3:32][N:33]([CH3:34])[C:24]1[CH:25]=[CH:26][C:21]([C:20]([NH:19][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([C:8]([F:17])([C:13]([F:14])([F:16])[F:15])[C:9]([F:12])([F:10])[F:11])=[CH:5][C:4]=2[CH3:18])=[O:31])=[CH:22][C:23]=1[N+:28]([O-:30])=[O:29]
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CNC
Solvent: O
Solvent: CC#N
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(N(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-4-fluoro-3-nitrobenzamide (5.0 g, 11 mmol) (prepared according to WO 05/073165) in acetonitrile (100 ml) was added a solution of N,N-dimethylamine in water (40% by weight) (3.55 ml, 28 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes. Then the reaction mixture was concentrated and the residue purified by chromatography over silica gel (eluent: ethyl acetate) to give 4-dimethylamino-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-3-nitrobenzamide (5.3 g, 100% yield).
Reaction SMILES: C1C(/C=N/O)=CC=[N+](C[N+]2C=CC(/C=N/[OH:16])=CC=2)C=1.[Br-].[Br-].[C:22]([CH:25]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]1[C:32](=NOC)[CH2:33][CH2:34][CH:35]=1)([OH:24])=[O:23]>>[C:22]([CH:25]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]1[C:32](=[O:16])[CH2:33][CH2:34][CH:35]=1)([OH:24])=[O:23]
Reactant: O/N=C/c1cc[n+](C[n+]2ccc(/C=N/O)cc2)cc1
Reactant: CON=C1CCC=C1CCCCCC(C(=O)O)c1ccccc1
Agent: [Br-]
Product: O=C1CCC=C1CCCCCC(C(=O)O)c1ccccc1

Procedure:
Methoxime cleavage of 2-(6-carboxy-6-phenylhexyl)-1 -methoxiimino-2-cyclopentene (Example 466) in the manner of Example 38 is productive of the subject ketone.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[C:20]3[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=3[CH:18]=[C:17]([C:26]([O:28][CH3:29])=[O:27])[CH:16]=2)=[CH:10][N:9]=1)=[O:7])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:29][O:28][C:26]([C:17]1[CH:16]=[C:15]([O:14][C:11]2[CH:12]=[CH:13][C:8]([C:6]([OH:7])=[O:5])=[N:9][CH:10]=2)[C:20]2[CH2:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[CH:18]=1)=[O:27]
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)OC(C)(C)C)nc2)c2c(c1)OC(C)(C)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(Oc2ccc(C(=O)O)nc2)c2c(c1)OC(C)(C)C2

Procedure:
A solution of 5-(6-methoxycarbonyl-2,2-dim ethyl-2,3-dihydro-benzofuran-4-yloxy)-pyridine-2-carboxylic acid tert-butyl ester (163a) (260 mg, 0.65 mmol) in 4 mL CH2Cl2 and 2 mL TFA was stirred at room temperature for 2 hr. The mixture was concentrated, dried under vacuum, and taken to the next step as it is.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10]2[C:21]3[C:20]4[C@@H:19]([CH2:22][CH2:23][OH:24])[CH2:18][CH2:17][C:16]=4[S:15][C:14]=3[N:13]=[CH:12][N:11]=2)[CH2:5][CH2:4]1.Cl[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:28].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)Cl>[OH:24][CH2:23][CH2:22][C@H:19]1[CH2:18][CH2:17][C:16]2[S:15][C:14]3[N:13]=[CH:12][N:11]=[C:10]([O:9][CH:6]4[CH2:5][CH2:4][CH:3]([N:2]([CH3:1])[CH2:26][C:27]([N:29]5[CH2:33][CH2:32][CH2:31][CH2:30]5)=[O:28])[CH2:8][CH2:7]4)[C:21]=3[C:20]1=2
Reactant: CNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](CCO)CC4)CC1
Reactant: O=C(CCl)N1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(CC(=O)N1CCCC1)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CCO)CC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 2-[(3R)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]ethan-1-ol (120 mg, 0.35 mmol, 1.00 equiv) in distilled DMF (5 mL) was added 2-chloro-1-(pyrrolidin-1-yl)ethan-1-one (75 mg, 0.51 mmol, 1.50 equiv) and potassium carbonate (26 mg, 0.19 mmol, 2.00 equiv) at room temperature. The resulting solution was stirred overnight at room temperature. The reaction mixture was diluted with DCM (100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with methanol/DCM (1:10) to afford the desired 2-[(4-[[(3R)-3-(2-hydroxyethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)(methyl)amino]-1-(pyrrolidin-1-yl)ethan-1-one (130 mg, 82%) as a white solid. MS (ES): m/z 459 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 8.47 (1H, s), 5.32-5.20 (1H, m), 3.66 (2H, t), 3.58 (2H, t), 3.50-3.41 (3H, m), 3.37 (2H, s), 3.15-3.05 (1H, m), 3.00-2.92 (1H, m), 2.75-2.60 (2H, m), 2.37 (3H, s), 2.33-2.15 (4H, m), 2.03-1.88 (6H, m), 1.71-1.54 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29](=[N:31][OH:32])[NH2:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C1CCN2C(=NCCC2)CC1.[C:44](N1C=CN=C1)(N1C=CN=C1)=[O:45]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:22][CH3:23])[CH2:24][CH3:25])[C:11](=[O:26])[C@:10]([CH2:28][C:29]3[NH:30][C:44](=[O:45])[O:32][N:31]=3)([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCC(CC)N1C(=O)[C@@](C)(CC(N)=NO)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: CCC(CC)N1C(=O)[C@@](C)(Cc2noc(=O)[nH]2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a solution of 385 mg (0.81 mmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)-N′-hydroxyacetimidamide (Example 82, Step C) in dioxane (12.5 mL) was added 211 μL (1.41 mmol) of DBU and 262 mg (1.62 mmol) of 1,1′-carbonyldiimidazole. The resulting colorless solution was heated at 100° C. for 25 min, and then was quenched with water and extracted with EtOAc. The organic layer was washed with saturated aqueous sodium chloride, and then was dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by reversed phase prep. HPLC (Sunfire™ Prep C18 OBD 10 μm column (Waters, Milford, Mass.), gradient elution of 55% MeCN in water to 80% MeCN in water over a 35 min period, where both solvents contain 0.1% TFA) provided the title compound as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.ClC1C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)=C2N=[C:16]([C:18]3[CH:23]=C[C:21]([CH2:24][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:20][CH:19]=3)NC2=NC=1.[NH2:42][C:43]1[C:48]([NH2:49])=[C:47]([NH:50][C@@H:51]2[C@@H:56]3[CH2:57][C@@H:53]([CH:54]=[CH:55]3)[C@@H:52]2[C:58]([NH2:60])=[O:59])[C:46]([Cl:61])=[CH:45][N:44]=1>>[Cl:61][C:46]1[C:47]([NH:50][C@@H:51]2[C@@H:56]3[CH2:57][C@@H:53]([CH:54]=[CH:55]3)[C@@H:52]2[C:58]([NH2:60])=[O:59])=[C:48]2[N:49]=[C:23]([C:18]3[CH:19]=[CH:20][CH:21]=[C:24]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)[CH:16]=3)[NH:42][C:43]2=[N:44][CH:45]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4cccc(N5CCOCC5)c4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 69 %

Procedure:
In the same fashion as for Compound III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 3-morpholin-j4-yl-benzaldehyde were reacted to produce the title compound (69%). 1H NMR (d-chloroform): 15.96 (br s, 1H) 8.37 (d, J=9 Hz, 1H), 7.83 (s, 1H), 7.71 (s, 1H), 7.59 (d, J=8 Hz, 1H), 7.40 (t, J=8 Hz, 1H), 7.06 (dd, J=2.8 Hz, 1H), 6.48 (m, 1H), 6.42 (m, 1H), 6.07 (br s, 1H), 5.86 (br s, 1H), 5.37 (t, J=8 Hz, 1H), 3.94 (m, 4H), 3.33 (m, 4H), 3.17 (s, 1H), 3.03 (s, 1H), 2.71 (d, J=8 Hz, 1H), 2.31 (d, J=9 Hz, 1H), 1.67 (d, J=9 Hz, 1H). MS: 466.07 (M+H). HPLC retention time: 2.41 minutes (G Method).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([OH:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br.Br[CH2:37][C:38]1[CH:47]=[C:46]2[C:41]([CH:42]=[CH:43][CH:44]=[N:45]2)=[CH:40][CH:39]=1.[H-].[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:37][C:38]2[CH:47]=[C:46]3[C:41]([CH:42]=[CH:43][CH:44]=[N:45]3)=[CH:40][CH:39]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2O)cc1
Reactant: BrCc1ccc2cccnc2c1
Agent: Br
Agent: [H-]
Agent: [Na+]
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3cccnc3c2)cc1

Procedure:
reacting the product of step c) with 7-bromomethyl-quinoline hydrobromide and sodium hydride to yield (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-(quinolin-7-yl-methoxy)-piperidine-1-carboxylic acid tert-butylester;
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]1[S:22][CH:23]=[N:24][N:25]=1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCOCC1>[CH2:1]([O:8][C:9]([NH:11][CH:12]([C:17]([NH:20][C:21]1[S:22][CH:23]=[N:24][N:25]=1)=[O:19])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CC(NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1nncs1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: CC(C)CC(NC(=O)OCc1ccccc1)C(=O)Nc1nncs1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.7 %

Procedure:
26.5 g of N-benzyloxycarbonyl-DL-leucine and 10 g of 2-amino-1,3,4-thiadiazole were dissolved in 80 ml of dioxane, to which was added dropwise 20 ml of a dioxane solution of 20.6 g of N,N'-dicyclohexylcarbodiimide, followed by stirring at room temperature for 24 hours. The solvent was removed from the reaction solution by distillation under reduced pressure, and the residue was recrystallized from diluted ethanol to obtain 20.9 g (yield: 56%) of 2-(N-benzyloxycarbonyl-DL-leucylamino)-1,3,4-thiadiazole as colorless crystals having a melting point of 121° C. (dec.).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[C:16](Cl)([N:18]=[C:19]=[O:20])=[O:17]>>[O:17]=[C:16]1[NH:18][C:19](=[O:20])[C:7]2[CH2:6][O:5][CH2:4][CH:3]([C:8]3[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=3)[C:2]=2[O:1]1
Reactant: N#Cc1ccc(C2COCCC2=O)cc1
Reactant: O=C=NC(=O)Cl
Product: N#Cc1ccc(C2COCc3c2oc(=O)[nH]c3=O)cc1

Procedure:
4-(4-oxotetrahydro-2H-pyran-3-yl)benzonitrile (Intermediate AA(2)) was reacted as described in Intermediate X(3) with carbonisocyanatidic chloride to give 4-(2,4-dioxo-2,3,4,5,7,8-hexahydropyrano[3,4-e][1,3]oxazin-8-yl)benzonitrile (Intermediate AA(3)). LC-MS (M+H)+=271.1. 1H NMR (400 MHz, CDCl3) δ ppm 7.57-7.78 (m, 2H) 7.41-7.51 (m, 2H) 4.61-4.75 (m, 1H) 4.50 (dd, J=15.49, 2.14 Hz, 1H) 4.04-4.20 (m, 2H) 3.78 (br. s., 1H).