Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30]>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=2)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc(C(F)(F)F)c2)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 3-Trifluoromethyl-benzoic acid. LC-MS (basic): tR=0.98 min; [M+H]+=520.3.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[C:12]([O:13][CH3:14])=[CH:11][C:10]([C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=2[O:19][CH3:20])[N:6]=1.[C:21]([O:25][C:26]([CH2:28][N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[C:30]1[C:38](O)=[O:39])=[O:27])([CH3:24])([CH3:23])[CH3:22].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl.O>[F:18][C:15]([F:16])([F:17])[C:10]1[CH:11]=[C:12]([O:13][CH3:14])[C:7]([C:5]2[N:6]=[C:2]([NH:1][C:38]([C:30]3[N:29]([CH2:28][C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[C:37]4[C:32]([CH:31]=3)=[CH:33][CH:34]=[CH:35][CH:36]=4)=[O:39])[S:3][CH:4]=2)=[C:8]([O:19][CH3:20])[CH:9]=1
Reactant: CC(C)(C)OC(=O)Cn1c(C(=O)O)cc2ccccc21
Reactant: COc1cc(C(F)(F)F)cc(OC)c1-c1csc(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1cc(C(F)(F)F)cc(OC)c1-c1csc(NC(=O)c2cc3ccccc3n2CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.3 %

Procedure:
A mixture of 0.609 g of 2-amino-4-(4-trifluoromethyl-2,6-dimethoxyphenyl)thiazole, 0.606 g of N-(tert-butoxycarbonylmethyl)-2-indolecarboxylic acid, 1.062 g of BOP and 0.243 g of triethylamine in 30 ml of DCM is stirred at r.t. for 24 hours. 50 ml of water are then added, and the organic phase is separated after settling has taken place, dried over sodium sulphate and evaporated under vacuum. The residue is chromatographed on silica H, eluting with a DCM/AcOEt (100:5; v/v) mixture. 0.79 g of the expected product is obtained after crystallization in ether, m.p.=214°-216° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH2:13][CH2:12][CH2:11][CH2:10][C:4]=2[Se:5][C:6]=1[C:7]([NH2:9])=[O:8].[N:14]([O-])=O.[Na+]>S(=O)(=O)(O)O>[N:1]1[C:2]2[C:3]3[CH2:13][CH2:12][CH2:11][CH2:10][C:4]=3[Se:5][C:6]=2[C:7](=[O:8])[NH:9][N:14]=1
Reactant: O=N[O-]
Reactant: NC(=O)c1[se]c2c(c1N)CCCC2
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=c1[nH]nnc2c3c([se]c12)CCCC3
Temperature: 0 °C
Reaction time: 2 h
Yield: 30.9 %

Procedure:
To an ice cold (0° C.) solution of 3-amino-4,5,6,7-tetrahydrobenzo[1,2-b]selenophene-2-carboxamide (1.4 g, 5.73 mmol) in concentrated sulfuric acid (10 mL) was added a cold (0° C.) solution of sodium nitrite (0.43 g, 6.31 mmol) in concentrated sulfuric acid (3 mL) for 10 min (while adding, the temperature should keep between −5-0° C.). After addition, the mixture was stirred at 0° C. for 2 h. The reaction mixture was poured into crushed ice slowly with stirring for 15 min and stirred at the same temperature for 15 min. The solution was extracted with ethyl acetate (3×100 mL) and the combined EtOAc layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent to give the product as a pale brown color solid (450 mg, 31%), mp 150-152° C. 1H NMR (400 MHz, DMSO-d6): δ 15.13 (1H, br s, —NH), 3.01-3.04 (2H, m, H-9), 2.90-2.92 (2H, m, H-6), 1.89-1.96 (4H, m, H-7,8); LC-MS (negative ion mode): m/z 252, 254 (M−H)−.
Reaction SMILES: [O:1]1[C:5](=[O:6])[CH2:4][CH:3]2[CH2:7][CH:8]3[C:13]([CH:12]=[CH:11][CH:10]=[CH:9]3)=[C:2]12.[OH-].[Na+].I([O-])(=O)(=O)=[O:17].[Na+].Cl>O.O.[Ru](Cl)(Cl)Cl.C(O)(C)C>[O:17]=[C:2]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:3]1[CH2:4][C:5]([OH:1])=[O:6]
Reactant: O=C1CC2CC3C=CC=CC3=C2O1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: O=C(O)CC1Cc2ccccc2C1=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a suspension of Tetrahydroindeno[1,2-b]furan-2-one (Example I5 or commercially available, 0.200 g, 1.15 mmol) in water (20 mL) was added sodium hydroxide (0.051 g, 1.26 mmol) and the solution was heated to 100° C. for one hour. The solution was cooled down to rt and Ruthenium(III) chloride hydrate (0.048 g, 0.230 mmol) was added followed by sodium periodate (0.368 mg, 1.72 mmol) in water (5 mL) dropwise. The solution was stirred at rt for 1 h and isopropanol was added (0.2 mL). The pH was acidified to 1 using 2M HCl and the reaction was filtered. The filtrate was extracted with dichloromethane (3*30 mL) and the combined organic layers were washed with water (30 mL), dried and concentrated to give (1-Oxo-indan-2-yl)-acetic acid (Pale yellow solid, 170 mg, 78%). C11H10O3; MW: 190.2. LCMS (method A) RT 1.16 min; ES− 189 (35%, MH+), 175 (70%), 145 (100%), 127 (90%). 1H NMR (400 MHz, CD3OD) δ 7.71 (1H, d), 7.65 (1H, t), 7.54 (1H, d), 7.41 (1H, t), 3.39-3.51 (1H, m), 2.83-3.02 (3H, m), 2.70 (1H, m) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:12]([O:24][CH2:25][CH2:26]Cl)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C[O-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:26][CH2:25][O:24][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CCCCCCCCCCCCOCCCl
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOCCOc1ccc(C(=O)OC)cc1

Procedure:
A mixture of 20.4 g (0.134 mol) of 4-hydroxybenzoic acid methylester, 200 ml of dimethyl formamide, 40 g (0.160 mol) of 2-dodecyloxy ethylchloride (from 2-dodecyloxy ethanol and thionyl chloride) and 8.6 g (0.160 mol) of sodium methylate was heated for 7 hours to boiling temperature and, after cooling and removal of the sodium chloride by filtration, was evaporated to dryness. The residue was dissolved in methylene chloride and subjected to column chromatography (silica gel, Merck using methylene chloride as the eluent). After recrystallization from methanol, the combined fractions after TLC gave 30 g (61% of the theoretical) of pure 4-(2-dodecyloxyethoxy)-benzoic acid methylester melting at 40° to 42° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:21]2[CH:31]=[CH:30][C:24]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])=[CH:23][CH:22]=2)=[N:6][C:7]=1[C:8](=O)[NH:9][NH:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1.O=P(Cl)(Cl)Cl>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:21]2[CH:22]=[CH:23][C:24]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])=[CH:30][CH:31]=2)=[N:6][C:7]=1[C:8]1[O:19][C:11]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)=[N:10][N:9]=1
Reactant: Cc1ccc(C(=O)NNC(=O)c2nc(-c3ccc(C(=O)N(C)C)cc3)cnc2N)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(-c2nnc(-c3nc(-c4ccc(C(=O)N(C)C)cc4)cnc3N)o2)cc1
Temperature: 25 °C
Yield: 24.6 %

Procedure:
A solution of 4-[5-amino-6-[[(4-methylbenzoyl)amino]carbamoyl]pyrazin-2-yl]-N,N-dimethyl-benzamide (90 mg, 0.2151 mmol) and POCl3 (3.298 g, 2.005 mL, 21.51 mmol) was heated at 110° C. for 2 h. After this time the reaction mixture was cooled to room temperature and ice added. Once all of the ice had melted the reaction mixture was extracted with dichloromethane (3×5 mL) and the combined organics dried over MgSO4 and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The product fractions combined and lyophilised to leave the product as a yellow solid (21.2 mg, 20% yield); 1H NMR (400.0 MHz, DMSO) d 2.22 (s, 3H), 2.75 (m, 6H), 7.26 (m, 2H), 7.32 (m, 2H), 7.58 (br s, 2H), 7.83 (m, 2H), 7.95 (m, 2H) and 8.77 (1H, s); MS (ES+) 401.15
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C@@H:9]3[N:10]([CH3:19])[C:11]4[C:16]([C@:8]3([CH3:20])[CH2:7][CH2:6]2)=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=4)[CH2:3][CH2:2]1.B(Br)(Br)Br>C(Cl)(Cl)Cl>[CH:1]1([CH2:4][N:5]2[C@@H:9]3[N:10]([CH3:19])[C:11]4[C:16]([C@:8]3([CH3:20])[CH2:7][CH2:6]2)=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=4)[CH2:2][CH2:3]1
Reactant: COc1ccc2c(c1)[C@]1(C)CCN(CC3CC3)[C@@H]1N2C
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Product: CN1c2ccc(O)cc2[C@]2(C)CCN(CC3CC3)[C@H]12

Procedure:
The title compound is prepared in the same manner as described for the 1-(2-phenylethyl) analog of Example 45 except that 2.72 g of (3aS-cis)-1-cyclopropylmethyl-1,2,3,3a,8,8a-hexahydro-5-methoxy-3a,8-dimethylpyrrolo[2,3-b]indole is reacted as a starting material with 10.1 g of boron tribromide in chloroform.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:14]=[CH:13][C:9]2[O:10][CH2:11][O:12][C:8]=2[CH:7]=1)=[O:5].[C:15]1([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.O>CN(C=O)C>[C:15]1([N:21]2[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][C:4]([C:6]3[CH:14]=[CH:13][C:9]4[O:10][CH2:11][O:12][C:8]=4[CH:7]=3)=[O:5])[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(CCCl)c1ccc2c(c1)OCO2
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(CCN1CCN(c2ccccc2)CC1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 10 h
Yield: 83.8 %

Procedure:
5-(3-Chloropropionyl)-1,3-benzodioxole (3 g) and N-phenylpiperazine (2.4 g) were dissolved in DMF (20 ml), triethylamine (1.7 g) was then added and the mixture was stirred for 10 hours at room temperature. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was crystallized from methanol and the resulting crystals were recrystallized from ethanol to give 5-[3-(4-phenyl-1-piperazinyl)propionyl]-1,3-benzodioxole (4.0 g, 84% yield). The characteristics of this compound are shown in Table 3 as Compound 47.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:31])[CH:11]([CH2:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[OH:8][NH:9][C:10](=[O:31])[CH:11]([CH2:19][S:20]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)(=[O:21])=[O:22])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccc(S(=O)(=O)CC(Cc2ccccc2)C(=O)NOCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)CC(Cc2ccccc2)C(=O)NO)cc1

Procedure:
N-benzyloxy-2-[(4-methoxybenzenesulfonyl)methyl]-3-phenyl- propionamide (1.25 g, 2.85 mmol) is dissolved in 45 mL of ethanol. To this is added 0.36 g of palladium hydroxide on carbon (Pearlman's catalyst), and the suspension is placed in a shaker under 15 psi of hydrogen for 2.25 hours. The catalyst is filtered off, washing with ethanol, and the ethanol solution is concentrated in vacuo to afford, after evaporation from methylene chloride, 0.875 g of the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][N:16]=2)[CH2:11][CH:10]([NH:24]C(=O)OCC2C=CC=CC=2)[C:9]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.CO.[Pd]>[NH2:24][CH:10]1[CH2:11][C:12]2[C:17](=[N:16][CH:15]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:13]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]1=[O:35]
Reactant: O=C(NC1Cc2cc(-c3ccccc3)cnc2N(Cc2ccccc2)C1=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: NC1Cc2cc(-c3ccccc3)cnc2N(Cc2ccccc2)C1=O
Yield: 99.3 %

Procedure:
To a solution of 1I (170 mg, 0.367 mmol) in THF (5 mL) and MeOH (5 mL) at RT was added palladium 5% wt. on activated carbon (85 mg). The reaction mixture was stirred under a hydrogen balloon for lh. The reaction was filtered and the filtrate concentrated to give the title compound as a light yellowish oil (120 mg, 100%). LC/MS (method A): retention time=3.07 min, (M+H)+=330.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:20]=[CH:19][C:11]([C:12]([O:14]C(C)(C)C)=[O:13])=[C:10]([N:21]([CH:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)[C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH:9]=2)[CH2:4][CH2:3]1.[ClH:35].O1CCOCC1>ClCCl>[ClH:35].[ClH:35].[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:20]=[CH:19][C:11]([C:12]([OH:14])=[O:13])=[C:10]([N:21]([CH:28]3[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]3)[C:22](=[O:27])[C:23]([F:25])([F:24])[F:26])[CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCC(N(C(=O)C(F)(F)F)c2cc(N3CCN(C)CC3)ccc2C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CN1CCC(N(C(=O)C(F)(F)F)c2cc(N3CCN(C)CC3)ccc2C(=O)O)CC1
Reaction time: 1.5 h

Procedure:
tert-Butyl 4-(4-methylpiperazin-1-yl)-2-[(1-methylpiperidin-4-yl)(trifluoroacetyl)amino]benzoate (1.18 g, 2.435 mmol) was dissolved in dry dichloromethane (3 mL) under nitrogen atmosphere. A 4 M solution of HCl in dioxane (9.1 mL, 36.4 mmol, 15 eq) was then added dropwise and the mixture was stirred for 1.5 hours. A sticky solid was formed. 5 more equivalents of HCl were added and the mixture was stirred for 2 more hours. The solid was filtered, washed with DCM (10 mL) and diethyl ether (10 mL) and dried under vacuum at 60° C. for 2 hours. 1.06 g of title compound were obtained as a beige powder (87% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C@@H:4]1[C:6]([CH3:8])([CH3:7])[C@@H:5]1[C:9]([OH:11])=[O:10].[Br-].[Br-].[Br-].[Al+3]>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:12])=[CH:3][CH:4]1[C:6]([CH3:7])([CH3:8])[CH:5]1[C:9]([OH:11])=[O:10]
Reactant: CC(C)=C[C@H]1[C@@H](C(=O)O)C1(C)C
Agent: [Al+3]
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CC(C)=CC1C(C(=O)O)C1(C)C
Reaction time: 0.17 h
Yield: 98.5 %

Procedure:
To a solution of (+)-cis chrysanthemic acid (2.0 g) in toluene (20 ml) was added a solution of aluminum tribromide (32 mg) in toluene (2.2 ml) at room temperature under a nitrogen atmosphere. Irradiation with a xenon lamp (500 W) was made for 10 minutes under stirring. After the irradiation was over, the similar after-treatment as in Example 1 was applied to obtain chrysanthemic acid (1.97 g). The optical isomer ratio of the product was (+)-cis, 3.7%; (-)-cis, 3.1%; (+)-trans, 46.6%; and (-)-trans, 46.6%.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([Cl:20])=[CH:13][N:12]=1.O>C1(C)C(C)=CC=CC=1.CC1C=CC(CC)=CN=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:11]2[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([Cl:20])=[CH:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Cl
Reactant: NCc1ccc(Cl)cc1
Agent: CCc1ccc(C)nc1
Solvent: Cc1ccccc1C
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)cnc1NCc1ccc(Cl)cc1
Yield: 87 %

Procedure:
A solution of 20.9 g of 4-chlorobenzylamine and 15.7 g of 2,5-dichloro-3-nitropyridine in 250 ml of xylene and 20 ml of 2-methyl-5-ethylpyridine is refluxed for 30 hours. After cooling, water is added to the reaction mixture, the resulting mixture is then extracted with ethyl acetate and the organic phase is washed with a dilute solution of hydrochloric acid and dried over magnesium sulfate. The solvent is evaporated off under vacuum and the residue obtained crystallizes from isopropyl ether to give 21.1 g of 2-(4-chlorophenylmethylamino)-3-nitro-5-chloropyridine in the form of crystals melting at 120° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl.C(N(CC)CC)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]([CH:25]([CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[CH2:26][O:27][C:28]3[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=3[F:36])=[C:23]3[CH2:43][CH2:44][CH2:45][C:22]3=[N:21]2)=[CH:16][CH:15]=1>CN(C=O)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]([CH:25]([CH:37]3[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]3)[CH2:26][O:27][C:28]3[CH:35]=[CH:34][C:31]([C:32]4[N:1]=[N:2][NH:3][N:33]=4)=[CH:30][C:29]=3[F:36])=[C:23]3[CH2:43][CH2:44][CH2:45][C:22]3=[N:21]2)=[CH:16][CH:15]=1
Reactant: N#Cc1ccc(OCC(c2c3c(nn2-c2ccc(Cl)cc2)CCC3)C2CCCCC2)c(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Fc1cc(-c2nn[nH]n2)ccc1OCC(c1c2c(nn1-c1ccc(Cl)cc1)CCC2)C1CCCCC1
Temperature: 120 °C
Reaction time: 14 h
Yield: 60.5 %

Procedure:
Sodium azide (14 mg, 215 umol) and triethylamine hydrochloride (29 mg, 215 umol) were added to a solution of 4-{2-[2-(4-chloro-phenyl)-2,4,5,6-tetrahydro-cyclopentapyrazol-3-yl]-2-cyclohexyl-ethoxy}-3-fluoro-benzonitrile (20 mg, 43 umol; example 3) in DMF (0.5 ml). The solution was stirred at 120° C. for 14 h, poured onto ice water/1 N aqueous HCl solution 1/1 and extracted two times with iPrOAc. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. The solvent was removed under reduced pressure to give a solid which was crystallized from heptane/dichloromethane to obtain the title compound (13 mg, 26 umol; 59%) as off-white solid. MS: m/e=507.2 [M+H+].
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]([C:13]1[C:22]([CH3:23])=[C:21]([OH:24])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([F:25])[CH:19]=2)[CH:14]=1)=[O:12].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CC(C)=O>[CH3:9][O:10][C:11]([C:13]1[C:22]([CH3:23])=[C:21]([O:24][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([F:25])[CH:19]=2)[CH:14]=1)=[O:12]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc2ccc(F)cc2c(O)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COC(=O)c1cc2ccc(F)cc2c(OCc2ccccc2)c1C
Yield: 66.2 %

Procedure:
Benzyl bromide (10 mL, 82.51 mmol) was added to a mixture of 6-fluoro-4-hydroxy-3-methyl-naphthalene-2-carboxylic acid methyl ester (15.56 g, 66.43 mmol) and potassium carbonate (19.26 g, 136.6 mmol) in acetone (300 mL). The reaction mixture was heated at reflux for 3 hours. The acetone was removed in vacuo. The residue was diluted with water, and the resulting mixture was extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated. A concentrated solution of the crude product in 25% ethyl acetate in hexanes was loaded onto a Analogix SuperFlash™ column. Flash chromatography (25-50% ethyl acetate in hexanes) provided 14.27 g (66% yield) of 4-benzyloxy-6-fluoro-3-methyl-naphthalene-2-carboxylic acid methyl ester as a slightly yellow solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.34 (s, 1 H), 8.19 (dd, J=8.9, 5.9 Hz, 1 H), 7.64 (dd, J=10.7, 2.3 Hz, 1 H), 7.57 (d, J=6.6 Hz, 2 H), 7.36-7.54 (m, 4 H), 4.98 (s, 2 H), 3.89 (s, 3 H), 2.56 (s, 3 H).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:9][O:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([Br:25])=[CH:22][CH:23]=3)[CH:18]=[CH:17][C:16]=2[O:26][CH3:27])[C:4]1=[O:28].[C:29]([O:33][C:34]([N:36]([CH3:43])[C@@H:37]([CH2:41][CH3:42])[C:38](O)=[O:39])=[O:35])([CH3:32])([CH3:31])[CH3:30].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[Br:25][C:21]1[CH:20]=[C:19]2[C:24](=[CH:23][CH:22]=1)[C:15]([CH2:14][N:5]1[C:4](=[O:28])[C@@H:3]([NH:2][C:38](=[O:39])[C@@H:37]([N:36]([CH3:43])[C:34](=[O:35])[O:33][C:29]([CH3:30])([CH3:31])[CH3:32])[CH2:41][CH3:42])[CH2:9][O:8][C:7]3[CH:10]=[CH:11][CH:12]=[CH:13][C:6]1=3)=[C:16]([O:26][CH3:27])[CH:17]=[CH:18]2
Reactant: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](N)COc2ccccc21
Reactant: CC[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@@H](C(=O)N[C@H]1COc2ccccc2N(Cc2c(OC)ccc3cc(Br)ccc23)C1=O)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
A mixture of (S)-3-amino-5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one hydrochloride (54 mg, 116 μmol), (S)-2-(tert-butoxycarbonyl(methyl)amino)butanoic acid (27.8 mg, 128 μmol), DIEA (80.6 μl, 466 iumol), and HBTU (48.6 mg, 128 μmol) in DMF (388 μL) was stirred at RT for 30 min. The mixture was diluted with EtOAc, washed with sat. NaHCO3, H2O and brine, then dried over Na2SO4, and filtered. The filtrate was concentrated to give a residue that was purified by silica gel chromatography to provide tert-butyl (S)-1-((S)-5-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)-1-oxobutan-2-yl(methyl)carbamate (67.5 mg, 93%) as a white solid. MS m/z 648/650 (MNa)+
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[O:29][CH2:30][CH3:31])=[CH:11][CH:10]=1)#[N:2].C[Sn]([N:36]=[N+:37]=[N-:38])(C)C>C1(C)C=CC=CC=1>[CH2:30]([O:29][C:17]1[N:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]3[NH:38][N:37]=[N:36][N:2]=3)=[CH:14][CH:13]=2)[C:20]2[C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=1)[CH3:31]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCOc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: Cc1ccccc1
Product: CCOc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
A mixture of methyl 1-[(2′-cyanobiphenyl-4-yl)methyl]-2-ethoxybenzimidazole-7-carboxylate (1.85 g) and trimethyltin azide (2.80 g) in toluene (15 ml) were heated under reflux for one day. The reaction mixture was concentrated to dryness. To the residue were added methanol (50 ml) and 1N-HCl (20 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was adjusted to about pH 3-4 with 1N-NaOH. After removal of the solvent, the residual syrup was purified by column chromatography on silica gel to give crystals. Recrystallization from ethyl acetate-benzene gave colorless crystals (1.16 g, 56%), m.p. 191-193° C. (decomp.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH2:10]Cl)[C:3]=1[O:12][CH3:13].[C-:14]#[N:15].[K+].O>CS(C)=O>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH2:10][C:14]#[N:15])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: [C-]#N
Reactant: COc1cc(Br)c(OC)c(CCl)c1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(Br)c(OC)c(CC#N)c1
Reaction time: 2 h
Yield: 76.9 %

Procedure:
A solution of 1-Bromo-3-chloromethyl-2,5-dimethoxy-benzene 53 (7.0 g, 26.4 mmol) and KCN (1.7 g, 26.4 mmol) in DMSO (50 ml) was heated to 75° C. After 2 hr, the reaction was cooled and poured into water. The aqueous layer was extracted with EtOAc and the organic layer was dried and concentrated. The product was purified by column chromatography on silica gel (20% EtOac/Hex) to give 54 as an oil (5.2 g, 77%): 1H NMR (DMSO-d6) δ 7.20 (d, 1 H, J=3.0 Hz), 6.99 (d, 1 H, J=3.0 Hz), 4.00 (s, 2 H), 3.75 (s, 6 H)
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.Br[CH2:13][CH2:14][O:15][CH2:16][CH2:17]Br.[H-].[Na+].[I-].[K+]>>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:10]#[N:11])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:5][CH:4]=1
Reactant: BrCCOCCBr
Reactant: CSc1ccc(CC#N)cc1
Agent: [H-]
Agent: [I-]
Agent: [K+]
Product: CSc1ccc(C2(C#N)CCOCC2)cc1
Yield: 77 %

Procedure:
The title compound (5.5 g, 77%, solid after trituration in pentane) was prepared using 4-(methylthio)phenylacetonitrile, bis(2-bromoethyl)ether, sodium hydride and potassium iodide similarly to the procedure used for intermediate 56. Microanalysis: Found: C, 66.62; H, 6.46; N, 5.97%. C13H15NOS requires C, 66.92; H, 6.48; N, 6.00%.