Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[N:6]=[C:7]([CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[C:10]([O:17][CH3:18])[CH:9]=2)(=O)C.N.[Li+].[OH-].Cl[CH2:35][C:36]1[C:37]([NH:48][CH2:49][CH3:50])=[N:38][C:39]2[C:44]([CH:45]=1)=[CH:43][C:42]([O:46][CH3:47])=[CH:41][CH:40]=2>C(Cl)Cl.CO>[CH2:49]([NH:48][C:37]1[C:36]([CH2:35][C:14]2[C:13]3[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([O:15][CH3:16])[CH:12]=3)[C:7]([CH2:19][N:20]3[C:28](=[O:29])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]3=[O:30])=[N:6][C:5]=2[OH:4])=[CH:45][C:44]2[C:39](=[CH:40][CH:41]=[C:42]([O:46][CH3:47])[CH:43]=2)[N:38]=1)[CH3:50]
Reactant: COc1cc2cc(OC(C)=O)nc(CN3C(=O)c4ccccc4C3=O)c2cc1OC
Reactant: CCNc1nc2ccc(OC)cc2cc1CCl
Agent: N
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCNc1nc2ccc(OC)cc2cc1Cc1c(O)nc(CN2C(=O)c3ccccc3C2=O)c2cc(OC)c(OC)cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-((1,3-dioxoisoindolin-2-yl)methyl)-6,7-dimethoxyisoquinolin-3-yl acetate SIL 32166 (297 mg, 0.73 mmol) in dry CH2Cl2 (9 mL) in a 25 mL round-bottomed flask equipped with a magnetic stirrer was added a 7 N NH3 solution in MeOH (1 mL) and the reaction mixture was stirred for 4 h at RT then concentrated to dryness at 40° C. under vacuum. The solid was taken up in THF (7 mL) and transferred in a 20 mL microwave vial equipped with a magnetic stirrer before addition of a 2 N aq. LiOH solution (0.37 mL, 0.74 mmol) and 3-(chloromethyl)-N-ethyl-6-methoxyquinolin-2-amine SLA 28166 free base (240 mg, 0.96 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (80 mL) and the organic solution was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 97:3) followed by a second purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 0:100) gave 2-((4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-3-hydroxy-6,7-dimethoxyisoquinolin-1-yl)methyl)isoindoline-1,3-dione CCH 42006-1 as a yellow oil (75 mg, 32%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12](I)=[N:11][C:10]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.[Sn].[S:27]1[CH:31]=[CH:30][CH:29]=[CH:28]1.[F-].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:28]3[S:27][CH:31]=[CH:30][CH:29]=3)=[N:11][C:10]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: Cn1c(I)nc(-c2ccc(S(C)(=O)=O)cc2)c1Sc1ccc(Cl)cc1
Reactant: c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cn1c(-c2cccs2)nc(-c2ccc(S(C)(=O)=O)cc2)c1Sc1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A mixture of Example 133 compound (34 mg, 0.067 mmol), thiophene tin reagent (22.34 μl, 0.0704 mmol) and Pd(PPh3)4 (77.42 mg, 0.067 mmol) in dioxane (1 ml) was vacuumed and purged to N2 for 3 times, then reaction mixture was heated at 110° C. for 4 hrs. The reaction mixture was cooled to rt, added KF (sat, 1 ml), stirred at rt for one hour, filtered, washed with EtOAc, and separated to two layers. The organic layer was washed with brine, dried, filtered, concentrated, and separated by prep TLC (CH2Cl2:Hex:EtOAc=3:3:1) to afford 5-[(4-chlorophenyl)sulfanyl]-1-methyl-4-[4-(methylsulfonyl)phenyl]-2-(thiophen-2-yl)-1H-imidazole (25 mg). 1H NMR (500 MHz), [CDCl3]: 8.38 (m, 2H), 7.95 (m, 2H), 7.50 (m, 2H), 7.40 (m, 2H), 7.15 (m, 1H), 7.10 (m, 2H), 3.82 (s, 3H), 3.05 (s, 3H). LCMS: [M+1]+=461.0. Human FAAH lysate assay: IC50=16.5 nM.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH2:14])[CH:8]=1.[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]1[CH:25]=O>CO>[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH:14][CH2:25][C:17]2[O:16][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH:18]=2)[CH:8]=1
Reactant: COC(=O)CCc1cccc(CN)c1
Reactant: O=Cc1cc2ccccc2o1
Agent: Cl
Solvent: CO
Product: COC(=O)CCc1cccc(CNCc2cc3ccccc3o2)c1

Procedure:
The title compound of Step A was prepared from 3-(3-aminomethyl-phenyl)-propionic acid methyl ester hydrochloride salt, of Preparation 44, and benzofuran-2-carbaldehyde using the method described in Example 1, Step A except the imine was formed in MeOH at reflux over 3 h. 1H NMR (400 MHz, CDCl3) δ 7.50 (dd, 1H), 7.42 (d, 1H), 7.25-7.14 (m, 5H), 7.07 (d, 1H), 6.55 (d, 1H), 3.91 (s, 2H), 3.79 (s, 2H), 3.64 (s, 3H), 2.92 (t, 2H), 2.60 (t, 2H).
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].C(=O)([O-])[O-].[K+].[K+].[NH2:12][CH2:13][C:14]1([OH:27])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1>O.C(OCC)(=O)C>[O:4]=[C:3]1[NH:12][CH2:13][C:14]2([CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:18][CH2:19]2)[O:27][CH2:2]1
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CN)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CNC(=O)CO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Chloroacetyl chloride (4.88 mL) was added dropwise to a vigorously stirred mixture at 0° C. of potassium carbonate (17.43 g) in water (78 mL) and tert-butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate (10.4 g) in ethyl acetate (92 mL). After 30 minutes at 0° C. the mixture was extracted with ethyl acetate and the organic layer dried over sodium sulfate, filtered and the solvent evaporated under reduced pressure. The residue was dissolved in THF (200 mL) and added dropwise over 3 hours to a stirred solution under nitrogen and heated at reflux of potassium tert-butoxide (1M in tert-butanol, 75 mL) and THF (250 mL). The mixture was cooled to room temperature and allowed to stir for 18 hours. Most of the solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and brine, the aqueous layer was re-extracted with ethyl acetate and the combined organics were dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The residue was purified by trituration with a mixture of ether (30 mL) and isohexane (20 mL) to afford the subtitled product. Yield 8.20 g.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Cl.Cl[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.C(=O)(O)[O-].[Na+]>C(O)CC(C)C>[N:22]1[CH:23]=[CH:24][C:19]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:14])=[O:15])=[CH:9][CH:8]=3)[CH2:3][CH2:2]2)=[CH:20][CH:21]=1
Reactant: NS(=O)(=O)c1ccc(C2CCNCC2)cc1
Reactant: Clc1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)CCO
Product: NS(=O)(=O)c1ccc(C2CCN(c3ccncc3)CC2)cc1

Procedure:
A mixture of the product of part (iii) above (3.75 g), 4-chloropyridine hydrochloride (2.34 g), sodium bicarbonate (3.93 g) and isoamyl alcohol (60 ml) was heated under reflux for 30 hours and then evaporated. The residue was triturated with water and the mixture was filtered. The solid was washed well with water and crystallised from methanol/water to give the title compound (0.43 g), m.p. 295° (with decomp).
Reaction SMILES: [ClH:1].[OH:2][C@H:3]([CH3:22])[C@H:4]([NH:14]C(=O)OC(C)(C)C)[C:5]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[C:7]([F:13])[CH:6]=1.CCCCCC>O1CCOCC1>[ClH:1].[NH2:14][C@H:4]([C:5]1[CH:6]=[C:7]([F:13])[C:8]([F:12])=[C:9]([F:11])[CH:10]=1)[C@H:3]([OH:2])[CH3:22]
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)c1cc(F)c(F)c(F)c1
Agent: Cl
Solvent: CCCCCC
Solvent: C1COCCO1
Product: C[C@@H](O)[C@H](N)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 4 N hydrogen chloride in dioxane (10 mL) was added to a solution of tert-butyl [(1R,2R)-2-hydroxy-1-(3,4,5-trifluorophenyl)propyl]carbamate (2.85 g) in dioxane (10 mL) at room temperature, and the reaction solution was stirred at room temperature for five hours. Hexane (80 mL) was added to the reaction solution at room temperature, and the reaction solution was stirred at room temperature for 20 minutes. The resulting solid was separated by filtration to obtain (1R,2R)-1-amino-1-(3,4,5-trifluorophenyl)propane-2-ol hydrochloride (2.16 g). DIEA (1.59 mL), WSC (880 mg), and HOBT (620 mg) were added to a solution of (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}valeric acid trifluoroacetate (1.00 g) and (1R,2R)-1-amino-1-(3,4,5-trifluorophenyl)propan-2-ol hydrochloride (664 mg) in DMF (25 mL) at room temperature, and the reaction solution was stirred at room temperature for one hour. Ethyl acetate was added to the reaction solution, which was then sequentially washed with saturated sodium bicarbonate water, water, a saturated ammonium chloride solution, and brine. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The resulting solid was washed with heptane to obtain (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}valeric acid [(1R,2R)-2-hydroxy-1-(3,4,5-trifluorophenyl)propyl]amide (1.10 g). (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}valeric acid [(1R,2R)-2-hydroxy-1-(3,4,5-trifluorophenyl)propyl]amide (1.10 g) was dissolved in DMF (25 mL). 60% sodium hydride (104 mg) was added to the reaction solution at room temperature, and the reaction solution was stirred at room temperature for one hour. Ethyl acetate was added to the reaction solution, which was then sequentially washed with saturated sodium bicarbonate water, water, a saturated ammonium chloride solution, and brine. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system), solidified with ethyl acetate and heptane, and separated by filtration to obtain 780 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: B(Br)(Br)Br.C([O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:25][CH:24]=1)[N:18]([S:37]([C:40]1[C:41]([CH3:46])=[N:42][O:43][C:44]=1[CH3:45])(=[O:39])=[O:38])[CH2:17][CH2:16]2)C1C=CC=CC=1.CO>C(Cl)Cl>[CH3:46][C:41]1[C:40]([S:37]([N:18]2[CH2:17][CH2:16][C:15]3[C:20](=[CH:21][CH:22]=[C:13]([OH:12])[CH:14]=3)[CH:19]2[C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH2:31][N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:27][CH:28]=2)(=[O:39])=[O:38])=[C:44]([CH3:45])[O:43][N:42]=1
Reactant: Cc1noc(C)c1S(=O)(=O)N1CCc2cc(OCc3ccccc3)ccc2C1c1ccc(OCCN2CCCC2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Cc1noc(C)c1S(=O)(=O)N1CCc2cc(O)ccc2C1c1ccc(OCCN2CCCC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 35.1 %

Procedure:
A 1M solution of BBr3 in CH2Cl2 (0.095 ml, 0.095 mmol) was added slowly to a solution of 6-benzyloxy-2-(3,5-dimethylisoxazole-4-sulfonyl)-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline (0.037 g, 0.063 mmol) in anhydrous CH2Cl2 (10 ml) at 0° C. under N2. The reaction mixture was stirred at 0° C. for 1 hr, then warmed to rt and stirred at rt for 4 hr. MeOH (5 ml) was slowly added with stirring and the resulting solution was concentrated in vacuo to an orange residue. Purification by preparative TLC, eluting with EtOAc:MeOH (1:1), and then purification again by preparative TLC, eluting with EtOAc:MeOH (8:2), gave 0.011 g (35% yield) of white solid.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]2[N:25]3[C:20]([C:21]([NH2:26])=[N:22][CH:23]=[N:24]3)=[C:19]([C:27]3[CH:28]=[CH:29][C:30]4[C:34]([CH:35]=3)=[N:33][N:32]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:31]=4)[CH:18]=2)[CH2:12]1)=O)C1C=CC=CC=1.Cl>>[CH2:36]([N:32]1[CH:31]=[C:30]2[C:34]([CH:35]=[C:27]([C:19]3[CH:18]=[C:17]([C@@H:13]4[CH2:14][CH2:15][CH2:16][NH:11][CH2:12]4)[N:25]4[C:20]=3[C:21]([NH2:26])=[N:22][CH:23]=[N:24]4)[CH:28]=[CH:29]2)=[N:33]1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: Nc1ncnn2c([C@@H]3CCCN(C(=O)OCc4ccccc4)C3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: Cl
Product: Nc1ncnn2c([C@@H]3CCCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 25 °C
Yield: 23.7 %

Procedure:
The product from step 1 (256 mg) was mixed with 6N aqueous HCl and heated to reflux for 30 min (HPLC analysis shows complete consumption of SM) and then allowed to cool to rt. The mixture was concentrated in vacuo and then dissolved in water (1 mL) and acetonitrile was added drop wise with stirring (˜10 mL). The mixture was stirred and a precipitate began to form. The mixture was stirred for 1 hour and the precipitate was collected by filtration, washed with acetonitrile and dried in a vacuum oven overnight and this fraction (presumably HCl salt) was set aside. The filtrate was concentrated in vacuo and the process repeated (0.5 mL of water and 20 mL of acetonitrile). The mixture was stirred overnight and then cooled in an ice bath for 1 hour and the precipitate was collected by filtration and dried in a vacuum oven (set aside). The filtrate from this process was poured through a column containing an acidic ion exchange resin. The column was washed with acetonitrile and the product eluted by washing the column with 2M NH3 in MeOH. The filtrate was concentrated to give 46 mg of the title compound as a free base. 1H NMR (300 MHz, DMSO-d6) δ 8.75 (s, 1H), 7.89 (s, 1H), 7.79 (d, 1H), 7.68 (s, 1H), 7.39-7.23 (m, 5H), 7.14 (d, 1H), 6.58 (s, 1H), 5.63 (s, 2H), 3.30-3.12 (m, 2H), 2.92 (d, 1H), 2.58-2.30 (m, 3H), 2.06 (m, 1H), 1.69-1.43 (m, 2H). ES-MS m/z 424.2 [M+H]+, HPLC RT (min) 2.17. Spectral properties of the HCl salt: 1H NMR (300 MHz, DMSO-d6) 9.22 (m, 1H), 9.06 (m, 1H), 8.59 (s, 1H), 8.07 (s, 1H), 7.83 (d, 1H), 7.62 (s, 1H), 7.38-7.25 (m, 5H), 7.13 (d, 1H), 6.78 (s, 1H), 5.62 (s, 2H), 3.64 (m, 1H), 3.52 (d, 1H), 3.31 (d, 1H), 3.09 (dd, 1H), 2.90 (dd, 1H), 2.10 (d, 1H), 1.96-1.69 (m, 3H). ES-MS m/z 424.4 [M+H]+, HPLC RT (min) 2.01.
Reaction SMILES: [C:1]([OH:12])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[C:8]([OH:10])(=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12]
Reactant: Nc1ccccc1
Reactant: O=C(O)CCCCCCC(=O)O
Solvent: Cc1ccccc1
Product: O=C(O)CCCCCCC(=O)Nc1ccccc1

Procedure:
Suberic acid (Compound 1, 174.2 g, 1.0 mole), aniline (Compound 2, 85.8-94.9 g), and toluene (0.1-0.2 L) are combined, heated to reflux and refluxed for a minimum of 60 hours. The reaction is quenched at reflux by adjusting the pH to ≧11 with 10% sodium hydroxide solution. The aqueous phase is separated. The organic layer is combined with toluene (0.11-0.13 L) and water (0.3-0.4 L), and the aqueous layer is separated. The aqueous layers from the extractions and toluene (0.11-0.13 L) are combined, settled, and then separated. The aqueous layer is extracted twice with toluene (0.2-0.3 L) at 60-70° C. The aqueous layer is adjusted at 20-30° C. to a pH of 5.8-6.2, using hydrochloric acid and 10% sodium hydroxide solution as needed. The batch is filtered, washed with chilled water (0.2-0.3 L) and then washed with chilled isopropanol. The wet cake is dried at a maximum of 65° C. under vacuum to yield suberanilic acid.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:18]=[CH:17][CH:16]=[CH:15][C:9]=2[C:10]([O:12][CH2:13]C)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(C(CC)CNC1N=CC=CC=1C(OCC)=[O:27])C>>[CH:1]1([N:7]2[C:8]3[N:18]=[CH:17][CH:16]=[CH:15][C:9]=3[C:10](=[O:11])[O:12][C:13]2=[O:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cccnc1NC1CCCCC1
Reactant: CCOC(=O)c1cccnc1NCC(CC)CC
Product: O=c1oc(=O)n(C2CCCCC2)c2ncccc12

Procedure:
The title compound was prepared according to the procedure of Example 3B substituting the product of Example 81A for the product of Example 3A (0.171 g, 35%). 1H NMR (300 MHz, CDCl3) δ 1.37 (m, 4H), 1.73 (m, 2H), 1.91 (m, 2H), 2.47 (ddd, J=24.82, 12.32, 3.31 Hz, 2H), 5.28 (tt, J=12.27, 3.72 Hz, 1H), 7.24 (dd, J=6.99, 4.04 Hz, 1H), 8.41 (dd, J=7.72, 2.21 Hz, 1H), 8.70 (dd, J=4.78, 2.21 Hz, 1H).
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([CH:24]4[CH2:28][CH2:27][C:26](=[O:29])[CH2:25]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])(O)[CH2:4][CH2:3]1.[BH4-].[Na+]>>[F:30][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([CH:24]4[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:4][CH2:3]1
Reactant: O=C1CCC(c2ccc3c(C(=O)NCC4(O)CCC(F)(F)CC4)c(Cl)ccc3n2)C1
Agent: [BH4-]
Agent: [Na+]
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(C3CCC(O)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 136 using 6-chloro-2-(3-oxo-cyclopentyl)-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxycyclohexyl methyl)-amide and NaBH4. 1H NMR (400 MHz, DMSO-d6): δ 88.72-8.76 (bs, 1H), 8.05-8.10 (m, 1H), 7.94 (d, J=9.51 Hz, 1H), 7.72-7.76 (m, 1H), 7.54-7.63 (m, 1H), 4.68 (s, 2H), 4.25-4.26 (m, 1H), 3.31-3.40 (m, 3H), 2.48-2.50 (m, 1H), 1.95-2.32 (m, 4H), 1.81-1.92 (m, 3H), 1.72-1.79 (m, 2H), 1.63-1.71 (m, 5H). m/z: 439.2 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1.[CH3:9][N:10]([CH3:14])[C:11](Cl)=[O:12].[Cl-].[Al+3].[Cl-].[Cl-]>C1(C)C(C)=CC=CC=1>[CH3:9][N:10]([CH3:14])[C:11]([NH:1][C:2]1[S:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1)=[O:12]
Reactant: Cc1nc(N)sc1C
Reactant: CN(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1C
Product: Cc1nc(NC(=O)N(C)C)sc1C
Yield: 91.5 %

Procedure:
Using 2-amino-4,5-dimethylthiazole (1.28 g), N,N-dimethylcarbamoyl chloride (1.29 g), aluminum chloride (1.60 g), and xylene (40 ml), the reaction is run as in Example 1, whereby 1,1-dimethyl-3-(4,5-dimethyl-2-thiazolyl)urea (1.82 g) is obtained. Yield is 91.5%. Melting point is 202.5° to 204° C. (after recrystallization from ethyl acetate).
Reaction SMILES: [C:1](=[N:4][OH:5])([NH2:3])[CH3:2].[H-].[Na+].[Cl:8][C:9]1[C:10]([N:24]2[C:28]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)=[N:27][N:26]=[C:25]2[C:35](OCC)=O)=[C:11]2[C:16](=[CH:17][C:18]=1[Cl:19])[N:15]=[C:14]([O:20][CH3:21])[C:13]([O:22][CH3:23])=[N:12]2>C1(C)C=CC=CC=1>[Cl:8][C:9]1[C:10]([N:24]2[C:28]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)=[N:27][N:26]=[C:25]2[C:35]2[O:5][N:4]=[C:1]([CH3:2])[N:3]=2)=[C:11]2[C:16](=[CH:17][C:18]=1[Cl:19])[N:15]=[C:14]([O:20][CH3:21])[C:13]([O:22][CH3:23])=[N:12]2
Reactant: CCOC(=O)c1nnc(-c2cccnc2)n1-c1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12
Reactant: CC(N)=NO
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1nc2cc(Cl)c(Cl)c(-n3c(-c4cccnc4)nnc3-c3nc(C)no3)c2nc1OC
Yield: 81.6 %

Procedure:
Acetamide oxime (120 mg, 1.62 mmol) followed by sodium hydride (80% w/w dispersion in oil, 8 mg, 0.27 mmol) were added to a stirred suspension of 6,7-dichloro-2,3-dimethoxy-5-[3-ethoxycarbonyl-5-(3-pyridyl)-4H-1,2,4-triazol-4-yl]quinoxaline (Preparation 94, 250 mg, 0.53 mmol) in dry toluene (15 mL) at room temperature under nitrogen. The mixture was heated under reflux for 3.5 hours, cooled and the solution partitioned between ethyl acetate and brine. The aqueous phase was extracted with ethyl acetate (2×20 mL), the combined organic extracts dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, by gradient elution using hexane:ethyl acetate (7:3 changing to 1:1, by volume) to give the title compound (210 mg, 82%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH2:3][CH2:4][OH:5].F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([O:5][CH2:4][CH2:3][C:2]([F:7])([F:6])[F:1])=[CH:10][CH:11]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OCCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(OCCC(F)(F)F)cc1
Temperature: 100 °C
Yield: 27.3 %

Procedure:
To a solution of a 3,3,3-trifluoro-propan-1-ol (6.22 g) in acetonitrile (200 ml) kept at RT under an argon atmosphere were added 1-fluoro-4-nitro-benzene (10.1 g) and Cs2CO3 (28.7 g) and the mixture was heated to 100° C. for 18 h. The reaction mixture was cooled to RT and partitioned between AcOEt and ice water. The layers were separated, dried, over Na2SO4 and the solvent was evaporated. The residue was purified by flash chromatography (silica gel; eluent: AcOEt/heptane:gradient 3 to 5%) to afford 1-nitro-4-(3,3,3-trifluoro-propoxy)-benzene as light yellow liquid (3.5 g). MS (EI, m/e): 235.0 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:15])[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:7]=1[CH3:8].[CH2:16]([O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28](Cl)=[CH:29][CH:30]=[N:31]2)=[CH:26][C:25]=1[O:35][CH3:36])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH2:16]([O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([O:15][C:4]3[C:5]([C:9]4[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=4)=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=3)=[CH:29][CH:30]=[N:31]2)=[CH:26][C:25]=1[O:35][CH3:36])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cc(O)c(-c2cccnc2)nc1C
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccnc3)ccnc2cc1OCc1ccccc1
Temperature: 140 °C
Reaction time: 6 h
Yield: 87.6 %

Procedure:
5,6-Dimethyl-3-hydroxy-[2,3′]bipyridine (400 mg), 7-benzyloxy-4-chloro-6-methoxyquinoline (1.80 g), and 4-dimethylaminopyridine (732 mg) were suspended in o-dichlorobenzene (8 ml), and the suspension was stirred at 140° C. for 6 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (811 mg, yield 88%).