Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH3:20])=[C:16]([Br:19])[CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH2:20][Br:21])=[C:16]([Br:19])[CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cc2ccn(S(=O)(=O)c3ccccc3)c2cc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=S(=O)(c1ccccc1)n1ccc2cc(CBr)c(Br)cc21
Temperature: 25 °C
Yield: 46.6 %

Procedure:
Under a nitrogen stream, a solution of 1-benzenesulfonyl-6-bromo-5-methyl-1H-indole (40 mg, 0.11 mmol), N-bromosuccinimide (NBS) (22 mg, 0.12 mmol) and 2,2′-azobis(isobutyronitrile) (AIBN) (1 mg, 0.01 mmol) in carbon tetrachloride (0.5 mL) was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature, and then purified by silica gel column chromatography (developing solution=ethyl acetate:n-hexane (1:9)), to thereby obtain the titled compound (22 mg, 45%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]1([NH:17][C:18]([NH:20]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)=[S:19])[CH2:12][C@@H:11]([O:13][CH3:14])[CH2:10][C@H:9]1[CH2:15]O>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:12][C@@H:11]([O:13][CH3:14])[CH2:10][C@H:9]1[CH2:15][S:19][C:18]([NH2:20])=[N:17]2
Reactant: CO[C@H]1C[C@@H](CO)[C@](NC(=S)NC(=O)OCC2c3ccccc3-c3ccccc32)(c2ccccc2F)C1
Solvent: CO
Product: CO[C@H]1C[C@H]2CSC(N)=N[C@@]2(c2ccccc2F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
A solution of 9H-fluoren-9-ylmethyl ({[(1S*,2R*,4S*)-1-(2-fluorophenyl)-2-(hydroxymethyl)-4-methoxycyclopentyl]amino}carbonothioyl)carbamate (330 mg) in methanol (20 mL)-concentrated hydrochloric acid (1 mL) was heated under reflux for three hours. The reaction solution was concentrated under reduced pressure. Acetonitrile (10 mL) and piperidine (1 mL) were added to the residue at room temperature, and the mixture was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure. The resulting crude product was purified by NH-silica gel column chromatography to obtain the title compound (170 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:20]2[C:15](=[C:16]([N+:22]([O-:24])=[O:23])[C:17]([CH3:21])=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1.C(O)(C(F)(F)F)=O>C(O)(C)C>[CH3:21][C:17]1[C:16]([N+:22]([O-:24])=[O:23])=[C:15]2[C:20](=[CH:19][CH:18]=1)[C:11]([NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)=[N:12][CH:13]=[CH:14]2
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1ccc2c(Cl)nccc2c1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: Cc1ccc2c(Nc3ccc(C#N)cc3)nccc2c1[N+](=O)[O-]
Temperature: 22 °C
Yield: 89.6 %

Procedure:
A mixture of 4-aminobenzonitrile (4.0 g, 34 mmol), isopropanol (50 mL) and 1-chloro-6-methyl-5-nitroisoquinoline (5.0 g, 22 mmol) was stirred at RT (22° C.) and treated with TFA (5.0 mL, 67 mmol). The reaction mixture was stirred at 80° C. for 17 h, and allowed to cool to RT. The thick slurry was diluted with isopropanol (100 mL) and the solid precipitate was collected by suction filtration. The solid was washed with saturated NaHCO3 (2×100 mL), water (50 mL), Et2O (50 mL), and hexane (100 mL) and dried in a vacuum oven at 70° C. overnight to provide 4-(6-methyl-5-nitroisoquinolin-1-ylamino)benzonitrile (6.0 g, 88% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 305 [M+H]+.
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:18])[C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[C:8]([OH:15])[C:7]=1[CH:16]=[O:17].Cl>O>[OH:17][CH:16]1[C:7]2[C:6](=[C:11]([CH3:12])[C:10]([O:13][CH3:14])=[CH:9][C:8]=2[OH:15])[C:5](=[O:18])[O:4]1
Reactant: COC(=O)c1c(C)c(OC)cc(O)c1C=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1cc(O)c2c(c1C)C(=O)OC2O
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
A solution of 28 g of potassium hydroxide in 0.2 l of water was added to 44.8 g of 2-formyl-3-hydroxy-5-methoxy-6-methylbenzoic acid methyl ester. The mixture was warmed to 75° C. within 30 min and subsequently cooled to 5° C. Upon addition of 50 ml of 10N hydrochloric acid, a precipitate was formed immediately. The mixture was stirred at 0° C. for 30 min and then filtered. The solid material was washed with water and dried in vacuo. The crude product was triturated with 160 ml of hot ethyl acetate. The mixture was cooled and 0.9 l of hexane were added. The solid was isolated by filtration to yield 41.2 g of (RS)-3,4-dihydroxy-6-methoxy-7-methyl-1,3-dihydro-iso-benzofuran-1-one, m.p. >255° C. (dec.).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]4[S:21][CH:22]=[C:23]([C:25]([O:27]CC)=[O:26])[N:24]=4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O.CO>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]4[S:21][CH:22]=[C:23]([C:25]([OH:27])=[O:26])[N:24]=4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1csc(Cc2ccc3oc(-c4nc(C(C)(C)C)cs4)cc3c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1csc(-c2cc3cc(Cc4nc(C(=O)O)cs4)ccc3o2)n1
Yield: 93.5 %

Procedure:
A mixture of 4-tert-butyl-2-{5-{[4-(ethoxycarbonyl)-thiazol-2-yl]methyl}benzofuran-2-yl}thiazole (0.79 g) and sodium hydroxide (0.17 g) in a mixture of water (2 ml) and methanol (6 ml) was stirred under reflux for 3 hours. After being cooled, the resulting solution was concentrated under reduced pressure. The residue was dissolved in water and neutralized with diluted hydrochloric acid. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in reduced pressure. The residue was washed with a small amount of ethyl acetate to give 4-tert-butyl-2-{5-{[4-carboxythiazol-2-yl]methyl}benzofuran-2-yl}thiazole (0.69 g).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[NH2:32][S:33]([C:36]1[CH:46]=[CH:45][C:39]([CH2:40][NH:41][C:42](=[O:44])[CH3:43])=[CH:38][CH:37]=1)(=[O:35])=[O:34]>>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:32][S:33]([C:36]3[CH:37]=[CH:38][C:39]([CH2:40][NH:41][C:42](=[O:44])[CH3:43])=[CH:45][CH:46]=3)(=[O:34])=[O:35])=[O:24])=[CH:18][CH:19]=2)[N:3]=1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Reactant: CC(=O)NCc1ccc(S(N)(=O)=O)cc1
Product: CC(=O)NCc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3nc(C)c(-c4ccccc4)c3C)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and N-[4-(aminosulfonyl)benzyl]acetamide: 1H-NMR [CDCl3/CD3OD(4:1)]δ 7.90-7.87 (2H, m), 7.48-7.26 (11H, m), 4.44 (2H, s), 3.45-3.41 (2H, m), 2.87-2.82 (2H, m), 2.32 (3H, s), 2.27 (3H, s), 2.03 (3H, s).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)=[N:9][N:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:11]=1)=O.C(=O)(O)O.[NH2:35][C:36]([NH2:38])=[NH:37].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:10]2[CH:11]=[C:7]([C:5]3[CH:4]=[CH:3][N:35]=[C:36]([NH2:38])[N:37]=3)[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=3)=[N:9]2)=[CH:18][CH:17]=1
Reactant: N=C(N)N
Reactant: COc1ccc(Cn2cc(C(=O)/C=C/N(C)C)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Agent: O=C(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(-c3ccnc(N)n3)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Yield: 67.8 %

Procedure:
450 mg (1.1 mmol) of (2E)-3-(dimethylamino)-1-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]prop-2-en-1-one were dissolved in 10 ml of dry dimethylformamide and 1.2 g (6.66 mmol) of guanidine carbonate and 910 mg (6.66 mmol) of potassium carbonate were added. After 16 hours at 120° C. the solvent was removed in vacuo and the residue taken up with dichloromethane and washed with water. The organic phase was then dried over sodium sulphate and evaporated. The crude was finally purified by flash-chromatography on a silica gel column (CH2Cl2-CH3COCH3 9/1), giving 300 mg (68%) of the title compound.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[C:24]1([CH:30]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:31][C:32](O)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:32](=[O:33])[CH2:31][CH:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Product: O=C(CC(c1ccccc1)c1ccccc1)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1

Procedure:
N-Cyclopropyl-N-[1-(3,3-diphenylpropanoyl)piperidin-4-yl]-3-trifluoromethylbenzenesulfonamide was prepared from N-cyclopropyl-N-(piperidin-4-yl)-3-trifluoromethylbenzenesulfonamide and 3,3-diphenylpropanoic acid. LC: 100%. MS: m/z=557 (M+H+). 1H NMR (CDCl3): δ 8.11 (1H, s), 8.02 (1H, d), 7.84 (1H, d), 7.70 (1H, t), 7.23 (10H, m), 4.64 (2H, m), 3.98 (1H, m), 3.85 (1H, d), 3.00 (2H, m), 2.82 (1H, t), 2.37 (1H, t), 1.86 (1H, m), 1.60 (4H, m), 0.91 (1H, m), 0.72 (3H, m);
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([N+:15]([O-])=O)[CH:7]=1.[O:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][N:26]2[C:34]3[C:29](=[CH:30][C:31]([NH:35][C:36]([C:38]4[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=4)=[O:37])=[CH:32][CH:33]=3)[CH:28]=[CH:27]2)[CH2:20][CH2:19]1>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[N:12]=[C:42]([C:41]3[CH:40]=[CH:39][C:38]([C:36]([NH:35][C:31]4[CH:30]=[C:29]5[C:34](=[CH:33][CH:32]=4)[N:26]([CH2:25][CH2:24][N:21]4[CH2:20][CH2:19][O:18][CH2:23][CH2:22]4)[CH:27]=[CH:28]5)=[O:37])=[CH:45][CH:44]=3)[NH:15][C:8]=2[CH:7]=1
Reactant: O=Cc1ccc(C(=O)Nc2ccc3c(ccn3CCN3CCOCC3)c2)cc1
Reactant: COCCOc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Product: COCCOc1ccc2nc(-c3ccc(C(=O)Nc4ccc5c(ccn5CCN5CCOCC5)c4)cc3)[nH]c2c1

Procedure:
Compound 676 was prepared according to the procedure similar to that described in Scheme III from 1-(2-methoxyethoxy-3,4-dinitrobenzene and 4-(1-(2-morpholinoethyl)-5-indolylaminocarbonyl)benzaldehyde. [M+H]+ calcd for C31H33N5O4: 540.26; found: 540.10.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:54]([C:57]1[CH:58]=[C:59]([CH:61]=[CH:62][CH:63]=1)[NH2:60])([CH3:56])[CH3:55]>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:60][C:59]3[CH:61]=[CH:62][CH:63]=[C:57]([CH:54]([CH3:56])[CH3:55])[CH:58]=3)=[O:17])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CC(C)c1cccc(N)c1
Reactant: Nc1ncc2c(n1)CCN(c1cccc(C(=O)O)c1)C2
Agent: CN(C)C(On1nnc2ccccc21)=[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(C)c1cccc(NC(=O)c2cccc(N3CCc4nc(N)ncc4C3)c2)c1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 37 %

Procedure:
A mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (162 mg, 0.60 mmol), N,N-diisopropylethylamine (0.523 mL, 3.0 mmol), and HBTU (250 mg, 0.66 mmol) in 6.0 mL DMF was stirred at room temperature for 3 minutes, briefly warmed to approx. 50° C. to dissolve solids, stirred an additional 10 minutes at room temperature, then 3-isopropylaniline (0.127 mL, 0.90 mmol) added and the reaction heated at 65° C. After 2 hours the mixture was partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated to a solid. The solid was chromatographed eluting with EtOAc/MeOH. The resulting solid was subjected to an EtOAc/NaHCO3 work-up to remove any silica gel impurity and then recrystallized from EtOAc to give the title compound as a pale yellow-beige solid (86 mg, 37%). 1H NMR (DMSO-d6) δ: 10.09 (s, 1H), 8.13 (s, 1H), 7.64-7.66 (m, 1H), 7.58-7.63 (m, 1H), 7.50-7.53 (m, 1H), 7.32-7.40 (m, 2H), 7.18-7.29 (m, 2H), 6.96-7.01 (m, 1H), 6.41 (s, 2H), 4.29 (s, 2H), 3.65 (t, J=6.0 Hz, 2H), 2.88 (spt, J=7.0 Hz, 1H), 2.77 (t, J=5.9 Hz, 2H), 1.22 (d, J=7.0 Hz, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[C:17]([CH3:18])=[C:16]([N+:19]([O-])=O)[CH:15]=[C:14]([CH2:22][CH3:23])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:5])[CH3:2].[H][H]>C(O)C.[Pd]>[NH2:19][C:16]1[CH:15]=[C:14]([CH2:22][CH3:23])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:17]=1[CH3:18]
Reactant: [H][H]
Reactant: CCOC(=O)Nc1c(C)c([N+](=O)[O-])cc(CC)c1C(=O)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Nc1c(C)c(N)cc(CC)c1C(=O)OCC
Yield: 94.4 %

Procedure:
A solution of ethyl 2-ethoxycarbonylamino-6-ethyl-3-methyl-4-nitro-benzoate (35 mg) in absolute ethanol (80 ml) was hydrogenated over 10% palladium on charcoal at 50 psi. hydrogen on a Parr hydrogenator for 5 hrs. The catalyst was removed by suction filtration through Celite. The filtrate was evaporated to give an oil which was further purified by thick layer chromatography (30% ethyl acetate: pet. ether 30-60) to give ethyl 4-amino-2-ethoxycarbonylamino-6-ethyl-3-methyl-benzoate as a white solid (30 mg). IR (CH2Cl2): 3340, 1700 (br.), 1600 cm-1. H-NMR (CD3OD): 1.00-1.50 (overlapping peaks [3t], 9H, CH3CH2, 2CH3CH2O), 2.00 (s, 3H, CH3), 2.60 (q, 2H, CH2Ar), 4.15 (q, 2H, CH2), 4.30 (q, 2H, CH2), 6.60 (s, 1 H, ArH).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Br.[OH:14][C:15]1[CH:19]=[C:18]([N:20]2[C:24]3[CH:25]=[N:26][CH:27]=[CH:28][C:23]=3[N:22]=[CH:21]2)[S:17][C:16]=1[C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:22]1[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[N:20]([C:18]2[S:17][C:16]([C:29]([O:31][CH3:32])=[O:30])=[C:15]([O:14][CH2:6][C:5]3[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=3[O:3][C:2]([F:13])([F:12])[F:1])[CH:19]=2)[CH:21]=1
Reactant: FC(F)(F)Oc1ccccc1CBr
Reactant: COC(=O)c1sc(-n2cnc3ccncc32)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3ccncc32)cc1OCc1ccccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
110 mg of 2-(trifluoromethoxy)benzyl bromide is added to a mixture of 100 mg of methyl 3-hydroxy-5-(3H-imidazo[4,5-c]pyridin-3-yl)thiophene-2-carboxylate and 59.7 mg of potassium carbonate in 3 ml anhydrous DMF. The mixture is stirred for 14 h at room temperature. Ice water is added and the organic phase is extracted with dichloromethane. The organic phase is poured on a phase separator and the solvent is removed under vacuum. The residue is dissolved in ethyl acetate and filtered through a short plug of silica gel (eluent: ethyl acetate) to yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][S:26]([N:29]1[CH2:34][CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH2:31][CH2:30]1)(=[O:28])=[O:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH:31]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(C2=CCN(S(C)(=O)=O)CC2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(C2(C)Cc3cc(Cl)ncc3O2)CC1
Product: CC(C)(C)OC(=O)N1CCC(C2(C)Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine following a procedure analogous to that described in Example 28. LC (method 6): tR=1.03 min; Mass spectrum (ESI+): m/z=478 [M+H]+.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:25]([OH:27])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:28][C:29]([F:41])([F:40])[C:30]1[CH:31]=[C:32]([S:36](Cl)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1>>[F:41][C:29]([F:28])([F:40])[C:30]1[CH:31]=[C:32]([S:36]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]([C:25]([OH:27])=[O:26])[NH:18][C:16]([O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[O:17])(=[O:37])=[O:38])[CH:33]=[CH:34][CH:35]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Product: O=C(N[C@@H](CCCCNS(=O)(=O)c1cccc(C(F)(F)F)c1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 61 %

Procedure:
Nα-(9-fluorenylmethoxycarbonyl)-L-lysine was reacted with 3-trifluoromethylbenzenesulfonyl chloride under the conditions used in example 2 giving 61% of the title compound.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:12][C:8]=2[CH:7]=1)=[O:5].[CH2:22]([Mg]Cl)[CH2:23][CH3:24]>C1COCC1>[C:13]1([C:11]2[O:12][C:8]3[CH:7]=[C:6]([C:4](=[O:5])[CH2:22][CH2:23][CH3:24])[CH:20]=[CH:19][C:9]=3[N:10]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCC[Mg]Cl
Reactant: CON(C)C(=O)c1ccc2nc(-c3ccccc3)oc2c1
Solvent: C1CCOC1
Product: CCCC(=O)c1ccc2nc(-c3ccccc3)oc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
To a solution of N-methoxy-N-methyl-2-phenylbenzo[d]oxazole-6-carboxamide (1.57 g, 5.6 mmol) in THF (20 mL) was added n-PrMgCl (2.0M in ether, 4.2 mL, 8.4 mmol, 1.5 eq) at 0° C. The mixture was warmed up to room temperature then stirred for 1 h. The reaction was quenched with saturated aqueous NH4Cl then extracted with EtOAc (3×40 mL). Solvent was removed then crude product was purified by flash column chromatography (0-20% EtOAc in hexanes) to afford the title compound (1.07 g, 4.0 mmol, 72%).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([F:35])=[C:6]([CH:31]=[CH:32][C:33]=1[F:34])[NH:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:29][CH3:30])=[C:15]([O:18][CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]([OH:28])=O)[CH2:21][CH2:20]3)[CH:16]=2)[N:11]=[CH:10][N:9]=1.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[Cl:3][C:4]1[C:5]([F:35])=[C:6]([CH:31]=[CH:32][C:33]=1[F:34])[NH:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:29][CH3:30])=[C:15]([O:18][CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]([N:40]4[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]4)=[O:28])[CH2:21][CH2:20]3)[CH:16]=2)[N:11]=[CH:10][N:9]=1
Reactant: CN1CCNCC1
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3F)c2cc1OC1CCN(CC(=O)O)CC1
Agent: Cl
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3F)c2cc1OC1CCN(CC(=O)N2CCN(C)CC2)CC1
Yield: 56 %

Procedure:
[4-({4-(3-chloro-2,4-difluoroanilino)-7-methoxyquinazolin-6-yl}oxy)piperidin-1-yl]acetic acid dihydrochloride salt and N-methylpiperazine were converted to the title compound (126 mg, 56%) using the procedure according to Examples 6 to 10.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].S(Cl)([Cl:22])(=O)=O.CC(N=NC(C#N)(C)C)(C#N)C.C([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl>[Cl:22][CH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1cccc(C)c1C(=O)OCc1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cccc(CCl)c1C(=O)OCc1ccccc1

Procedure:
12.0 g of benzyl 2,6-dimethylbenzoate are initially charged into 50 ml of carbon tetrachloride admixed at room temperature with 5.4 g of sulfuryl chloride and 40 mg of AIBN. The mixture is stirred at reflux for 4–5 h. Afterwards, it is admixed with 40 ml of saturated NaHCO3 solution. After the phase separation, the organic phase is washed with 50 ml of 10% sodium sulfite solution, and the organic phase is then dried over magnesium sulfate. The product-containing solution is filtered trough silica gel and washed again with 20 ml of carbon tetrachloride. After distilling off the solvent in vacuo, the product obtained is a bright yellow oil. Yield: 8.0 g (73% of theory; 88.4 area %).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:11]([CH3:21])[C:12]=2[S:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:33]1[S:34][CH:35]=[CH:36][N:37]=1)CCC>C1(C)C=CC=CC=1.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:20][C:17]1[CH:18]=[CH:19][C:14]([S:13][C:12]2[N:11]([CH3:21])[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[N:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([C:33]3[S:34][CH:35]=[CH:36][N:37]=3)=[CH:3][CH:4]=2)=[CH:15][CH:16]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: Cn1c(-c2ccccn2)nc(-c2ccc(Br)cc2)c1Sc1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cn1c(-c2ccccn2)nc(-c2ccc(-c3nccs3)cc2)c1Sc1ccc(Cl)cc1
Temperature: 150 °C

Procedure:
A mixture of 2-{4-(4-bromophenyl)-5-[(4-chlorophenyl)thio]-1-methyl-1H-imidazol-2-yl}pyridine (Example 15, 200 mg, 0.438 mmol), 2-(tributylstannyl)-1,3-thiazole (0.138 mL, 0.438 mmol), and tetrakis (50 mg, 0.044 mmol) was dissolved in toluene and heated at 150° C. for 20 min via microwave irradiation. The solvent was evaporated and the residue purified via column chromatography to afford the title compound. 1H NMR (500 MHz, (CD3)2CO): δ 8.71 (d, 1H), 8.40 (d, 1H), 8.40 (d, 2H), 8.32 (d, 2H), 8.00 (m, 1H), 7.90 (d, 1H), 7.63 (d, 1H), 7.46 (m, 1H), 7.36 (d, 2H), 7.20 (d, 2H), 4.18 (s, 3H). LCMS: m/z 461.0 (M+H)+. Human FAAH lysate assay: IC50=14.3 nM.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:11]([OH:15])[C@H:10]([C:16]([O:18]CC)=[O:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>COC(C)(C)C.[OH-].[Na+]>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:11]([OH:15])[C@H:10]([C:16]([OH:18])=[O:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CCC[C@@H]1O
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H](O)[C@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.3 %

Procedure:
A mixture of 28.7 g of the compound prepared in Example 13 in 200 ml of tert-butyl methyl ether and 200 ml of 2N NaOH was stirred vigorously at room temperature for 4 hours and then at 50° C. for 20 hours. After cooling, the aqueous phase was extracted twice with 100 ml of tert-butyl methyl ether each time. The organic phases were discarded. The aqueous phase was acidified cautiously with about 70 ml of 6N HCl and extracted once with 200 ml of tert-butyl methyl ether and twice with 100 ml of tert-butyl methyl ether each time. All three organic phases were washed once with 50 ml of 10% sodium chloride solution, combined and dried over sodium sulphate. After removal of the solvent under reduced pressure (40° C./25 mbar) the brown viscous oil was dissolved in 60 ml of isopropyl ether at 60° C. and left to crystallize at -20° C. for 16 hours. The crystals were filtered off, washed with a small amount of isopropyl ether, cooled to -20° C. and dried at 40° C. for 5 hours and 25 mbar, yielding 12.0 g of (3R,4S)-4-hydroxy-azepan-1,3-dicarboxylic acid 1-tert-butyl ester of melting point 98.5-101.5° C.