Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:10]1([CH:16]([NH:33][C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][N:35]=2)[C:17]2[CH:18]=[N:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[N:21][CH:22]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.C(=O)=O.CO>ClCCl.O>[CH:10]1([CH:16]([NH:33][C:34]2[N:35]=[CH:36][C:37]([C:38]([NH:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:39])=[CH:41][CH:42]=2)[C:17]2[CH:18]=[N:19][C:20]([C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:27][CH:28]=3)=[N:21][CH:22]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C(O)c1ccc(NC(c2cnc(-c3ccc(C(F)(F)F)cc3)nc2)C2CCCCC2)nc1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C=O
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2cnc(-c3ccc(C(F)(F)F)cc3)nc2)C2CCCCC2)nc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of ethyl 3-aminopropionate hydrochloride (487 mg, 4.15 mmol), crude (+/−)-6-[(cyclohexyl{2-[4-(trifluoromethyl)phenyl]pyrimidin-5-yl}methyl)amino]nicotinic acid (948 mg, 2.08 mmol), hydroxybenzotriazole hydrate (318 mg, 2.08 mmol), and triethylamine (1.16 ml, 8.31 mmol) in dichloromethane (21 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (442 mg, 2.28 mmol). The reaction was stirred for 12 hours at ambient temperature. The reaction was diluted with water and the organic layer was separated. The aqueous layer was extracted with dichloromethane (2×) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified via ISCO MPLC (SiO2, 0-100% ethyl acetate in heptane) to yield the product. The enantiomers were separated by chiral SFC to afford the two products (Isomer 1=50 mg, 5% and isomer 2=50 mg, 5%) as solids. Column: Chiralcel OJ-H. Dimensions: 10 mm×250 cm. Mobile Phase: 70/30 CO2/methanol. Flow Rate: 10 mL/min. Modifier: none. Isomer 1: Retention time: 2.37 minutes. Isomer 2: Retention time: 2.95 minutes. 1H NMR (400 MHz, CDCl3, δ): 8.76 (s, 2H), 8.53 (d, J=8.2 Hz, 2H), 8.43 (d, J=2.0 Hz, 1H), 7.78 (dd, J=8.7, 2.2 Hz, 1H), 7.71 (d, J=8.2 Hz, 2H), 6.71 (t, J=5.8 Hz, 1H), 6.30-6.36 (m, 1H), 5.84 (br. s., 1H), 4.68 (t, J=6.9 Hz, 1H), 4.13 (q, J=6.9 Hz, 2H), 3.65 (q, J=5.9 Hz, 2H), 2.58 (t, J=5.8 Hz, 2H), 1.95 (d, J=12.3 Hz, 1H), 1.56-1.85 (m, 6H), 1.23 (t, J=7.0 Hz, 3H), 1.04-1.20 (m, 4H). MS (M+1): 556.4.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][N:11]2[C:14](=[O:30])[CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:18]([CH3:29])[CH2:17]2)=[CH:7][CH:6]=1)=O.[CH3:31][NH2:32]>CO>[C:25]([O:24][C:22]([N:19]1[CH2:20][CH2:21][N:16]([CH2:15][C:14]([N:11]2[C:12]3[C:8](=[CH:7][CH:6]=[C:5]([C:3](=[O:2])[NH:32][CH3:31])[CH:13]=3)[CH2:9][CH2:10]2)=[O:30])[CH2:17][C@H:18]1[CH3:29])=[O:23])([CH3:27])([CH3:26])[CH3:28]
Reactant: CN
Reactant: COC(=O)c1ccc2c(c1)N(C(=O)CN1CCN(C(=O)OC(C)(C)C)[C@H](C)C1)CC2
Solvent: CO
Product: CNC(=O)c1ccc2c(c1)N(C(=O)CN1CCN(C(=O)OC(C)(C)C)[C@H](C)C1)CC2
Temperature: 120 °C
Yield: 20 %

Procedure:
1-[2-((R)-4-tert-Butoxycarbonyl-3-methyl-piperazin-1-yl)-acetyl]-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester (200 mg, 0.48 mmol) was dissolved in 2.0 M methylamine in MeOH (2.4 mL) and heated under microwave irradiation at 120° C. for 4 h. The solvent was removed in vacuo and the resulting oil was purified by column chromatography on silica gel (gradient elution, 0-100% EtOAc/petrol), to give the title compound (39 mg, 20%) as a colourless solid, 1H NMR (Me-d3-OD): 8.58 (1H, s), 7.51 (1H, d), 7.33 (1H, d), 4.39-4.28 (2H, m), 4.23 (1H, d), 3.88-3.77 (1H, m), 3.31-3.14 (3H, m), 2.92 (3H, s), 2.84 (1H, d), 2.39-2.30 (1H, m), 2.24-2.12 (1H, m), 1.48 (9H, s), 1.30 (3H, d).
Reaction SMILES: I[C:2]1[O:3][CH:4]=[C:5]([C:7]2[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=2[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[N:6]=1>CCO.[Pd]>[O:3]1[CH:4]=[C:5]([C:7]2[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=2[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[N:6]=[CH:2]1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-c1coc(I)n1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1ccccc1-c1cocn1

Procedure:
Hydrogenolysis of the tert-butyl 2-(2-iodooxazol-4-yl)benzylcarbamate was performed using H-Cube, 10% Pd/C, full H2 Mode, at 25° in EtOH. Following completion the reaction was concentrated and the residue was purified via Biotage (0% to 10% gradient; EtOAc:Hex; 50 g-HP-silica gel column). Obtained 200 mg of tert-butyl 2-(oxazol-4-yl)benzylcarbamate. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.47 (s, 9H) 4.39 (s, 2H) 7.36 (ddd, J=7.26, 5.37, 1.77 Hz, 2H) 7.48-7.65 (m, 2H) 7.89 (d, J=1.01 Hz, 1H) 8.00 (s, 1H); MS[MH]+=275.2
Reaction SMILES: C[Al](C)C.[F:5][C:6]([F:17])([F:16])[O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][NH2:12].[Br:18][C:19]1[CH:20]=[C:21]([C:27]2[O:31][N:30]=[C:29]([C:32](OCC)=[O:33])[N:28]=2)[CH:22]=[C:23]([Br:26])[C:24]=1[OH:25].O>CCCCCC.C(Cl)(Cl)Cl>[Br:26][C:23]1[CH:22]=[C:21]([C:27]2[O:31][N:30]=[C:29]([C:32]([NH:12][CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[C:8]([O:7][C:6]([F:16])([F:17])[F:5])[CH:9]=3)=[O:33])[N:28]=2)[CH:20]=[C:19]([Br:18])[C:24]=1[OH:25]
Reactant: NCc1cccc(OC(F)(F)F)c1
Reactant: CCOC(=O)c1noc(-c2cc(Br)c(O)c(Br)c2)n1
Agent: C[Al](C)C
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: O=C(NCc1cccc(OC(F)(F)F)c1)c1noc(-c2cc(Br)c(O)c(Br)c2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61.4 %

Procedure:
Trimethylaluminum (0.11 mL of a 2 N solution in hexane, 0.22 mmol) was added to a stirred solution of 3-(trifluoromethoxy)benzyl amine (42 mg, 0.22 mmol) in anhydrous chloroform (2 mL) under nitrogen and the resulting solution was stirred at room temperature for 20 minutes. Ethyl 5-(3,5-dibromo-4-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylate (78 mg, 0.2 mmol) was then added in one portion and the reaction was stirred at 50° C. for 5 h before standing at room temperature overnight. Water (2 mL) was added followed by more chloroform (3 mL), the organic phase was separated and evaporated to dryness to give a yellow oil. This was purified by preparative HPLC to give the title compound (66 mg, 62%) as a colourless solid. 1H NMR δ (ppm) (DMSO-d6): 4.58 (2H, d, J=6.20 Hz), 7.31 (1H, d, J=8.20 Hz), 7.39-7.47 (2H, m), 7.53 (1H, t, J=7.91 Hz), 8.20 (2H, s), 10.07 (1H, t, J=6.24 Hz). LCMS (10 cm_apci_formic) tR 4.14 min; m/z 534/536/538 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([CH:6]=[C:7]([CH3:21])[C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([Cl:20])=[CH:12][CH:11]=1)[NH2:5].[Cl:23][C:24]1[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=1[C:26]([N:28]=[C:29]=[O:30])=[O:27]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([NH:5][C:29]([NH:28][C:26](=[O:27])[C:25]2[CH:31]=[CH:32][CH:33]=[CH:34][C:24]=2[Cl:23])=[O:30])[CH:6]=[C:7]([CH3:21])[C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([Cl:20])=[CH:12][CH:11]=1
Reactant: Cc1cc(N)c(C)c(Cl)c1Oc1ccc(Cl)c2ccccc12
Reactant: O=C=NC(=O)c1ccccc1Cl
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=O)NC(=O)c2ccccc2Cl)c(C)c(Cl)c1Oc1ccc(Cl)c2ccccc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
Into a solution containing 3.0 grams (9.0 mmol) of 3-chloro-4-(4-chloro-1-naphthoxy)-2,5-dimethylaniline prepared in Part B in 25 milliliters of toluene which solution was warmed to a temperature of 50° C. and placed under a nitrogen atmosphere was slowly added a solution containing 2.5 grams (13.8 mmol) of 2-chlorobenzoyl isocyanate in 5 milliters of toluene. After stirring for 1 hour at a temperature of 50° C. the reaction mixture was cooled to room temperature, placed in an ice bath, and filtered through a Buchner funnel. The collected solid was dried under vacuum at a temperature of 50° C. to afford 3.15 grams of 1-[3-chloro-4-(4-chloro-1-naphthoxy)-2,5-dimethylpheny 1]-3-(2- chlorobenzoyl)urea as a white solid having a melting point of 187° C. Elemental analysis of the white solid indicated the following:
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20]C)=[O:18])=[C:15]([OH:22])[C:14]([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=[CH:13][CH:12]=2)(=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:29]1C(OC)=C(C(CSC2C=CC=CC=2)=CC=1)C(OC)=O>>[O:25]1[CH:26]=[CH:27][C:23]([C:14]2[C:15]([O:22][CH3:29])=[C:16]([C:11]([CH2:10][S:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:12][CH:13]=2)[C:17]([O:19][CH3:20])=[O:18])=[CH:24]1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Reactant: COC(=O)c1c(CSc2ccccc2)ccc(Br)c1OC
Product: COC(=O)c1c(CSc2ccccc2)ccc(-c2ccoc2)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 36, starting from methyl 3-bromo-2-methoxy-6-(phenylthiomethyl)-benzoate (Intermediate 80) and used without further characterization.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:14][C:15]2([F:20])[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:11](O)=[O:12])[C:7](=[O:21])[CH:6]=1.[CH3:27][C:28]1([CH3:40])[O:32][C@H:31]([CH2:33][N:34]2[CH:38]=[CH:37][C:36]([NH2:39])=[N:35]2)[CH2:30][O:29]1.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)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:14][C:15]2([F:20])[CH2:16][CH2:17][CH2:18][CH2:19]2)[C:11]([NH:39][C:36]2[CH:37]=[CH:38][N:34]([CH2:33][C@@H:31]3[CH2:30][O:29][C:28]([CH3:40])([CH3:27])[O:32]3)[N:35]=2)=[O:12])[C:7](=[O:21])[CH:6]=1
Reactant: O=C(O)C(CC1(F)CCCC1)N1CC(Oc2c(F)cccc2F)=CC1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC3(F)CCCC3)N3CC(Oc4c(F)cccc4F)=CC3=O)n2)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a solution of 2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(1-fluoro-cyclopentyl)-propionic acid (0.264 g, 0.71 mmol) in dry N,N-dimethylformamide (6 mL) was added 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49 0.170 g, 0.86 mmol), and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.470 g, 1.06 mmol). To this mixture was added N,N-diisopropylethylamine (0.282 g, 2.18 mmol) and the resulting mixture stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with an ammonium chloride solution, a saturated sodium bicarbonate solution, saturated sodium chloride solution and then dried over magnesium sulfate. The solvents were evaporated and the residue was purified by AnaLogix flash chromatography (Supelco Flash Column 23 g, 50% to 60% ethyl acetate/hexanes) which afforded 2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-3-(1-fluoro-cyclopentyl)-propionamide (0.330 g, 84%) as a light brown oil: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.24 (s, 3H), 1.30 (s, 3H), 1.46-2.02 (m, 8H), 2.04-2.47 (m, 2H), 3.73 (dd, J=8.4, 6.0 Hz, 1H), 4.00 (dd, J=8.4, 6.5 Hz, 1H), 4.06-4.20 (m, 2H), 4.28-4.39 (m, 2H), 4.53 (d, J=18.7 Hz, 1H), 5.03 (s, 1H), 5.09 (dd, J=9.5, 4.4 Hz, 1H), 6.44 (d, J=2.1 Hz, 1H), 7.28-7.49 (m, 3H), 7.61 (s, 1H), 10.84 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:81])([C:67]1[CH:72]=[CH:71][C:70]([O:73][CH2:74][CH2:75][CH2:76][C:77]([F:80])([F:79])[F:78])=[CH:69][CH:68]=1)[O:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][C:16]([CH2:57][C:58]2[CH:63]=[CH:62][C:61]([N+:64]([O-])=O)=[CH:60][CH:59]=2)([CH2:47][C:48]2[CH:53]=[CH:52][C:51]([N+:54]([O-])=O)=[CH:50][CH:49]=2)[CH2:17][O:18][C:19](=[O:46])/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:45])([F:44])[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][C:40]([F:43])([F:42])[F:41])=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)=[O:13])=[CH:6][CH:5]=1>CN(C)C=O.O.[Zn]>[F:1][C:2]([F:81])([C:67]1[CH:72]=[CH:71][C:70]([O:73][CH2:74][CH2:75][CH2:76][C:77]([F:80])([F:79])[F:78])=[CH:69][CH:68]=1)[O:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][C:16]([CH2:47][C:48]2[CH:49]=[CH:50][C:51]([NH2:54])=[CH:52][CH:53]=2)([CH2:57][C:58]2[CH:63]=[CH:62][C:61]([NH2:64])=[CH:60][CH:59]=2)[CH2:17][O:18][C:19](=[O:46])/[CH:20]=[CH:21]/[C:22]2[CH:23]=[CH:24][C:25]([O:28][C:29]([F:44])([F:45])[C:30]3[CH:31]=[CH:32][C:33]([O:36][CH2:37][CH2:38][CH2:39][C:40]([F:41])([F:42])[F:43])=[CH:34][CH:35]=3)=[CH:26][CH:27]=2)=[O:13])=[CH:6][CH:5]=1
Reactant: O=C(/C=C/c1ccc(OC(F)(F)c2ccc(OCCCC(F)(F)F)cc2)cc1)OCC(COC(=O)/C=C/c1ccc(OC(F)(F)c2ccc(OCCCC(F)(F)F)cc2)cc1)(Cc1ccc([N+](=O)[O-])cc1)Cc1ccc([N+](=O)[O-])cc1
Agent: [Zn]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(CC(COC(=O)/C=C/c2ccc(OC(F)(F)c3ccc(OCCCC(F)(F)F)cc3)cc2)(COC(=O)/C=C/c2ccc(OC(F)(F)c3ccc(OCCCC(F)(F)F)cc3)cc2)Cc2ccc(N)cc2)cc1
Yield: 87.4 %

Procedure:
9.57 g (8.38 mmol) of 2,2-bis(4-nitrobenzyl)-3-{[(2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}phenyl)prop-2-enoyl]oxy}propyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}phenyl)prop-2-enoate are dissolved in a mixture of 54 mL of N,N-dimethylformamide and 6 mL water. 13.9 g (51.4 mmol) ferric chloride hexahydrate are added. 5.60 g (85.7 mmol) zinc powder is added portion wise within 60 minutes. The mixture is allowed to react for 2 hours. The reaction mixture is partitioned between ethyl acetate and water and filtrated. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Filtration of the residue on 400 g silica gel using toluene:ethyl acetate 1:3 as eluent and crystallization from ethyl acetate:hexane mixture yielded 7.93 g of 2,2-bis(4-aminobenzyl)-3-{[(2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}phenyl)prop-2-enoyl]oxy}propyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}phenyl)prop-2-enoate as yellow crystals.
Reaction SMILES: C(N1C2C=CC=CC=2NC1=O)(C)C.C(N(CC)CC)C.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.Cl.[CH2:35]([O:42][C:43]([C:45]([CH3:56])([CH3:55])[CH2:46][N:47]1[CH2:52][CH2:51][CH:50]([CH2:53][NH2:54])[CH2:49][CH2:48]1)=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[CH:57]([N:60]1[C:64]2[CH:65]=[CH:66][CH:67]=[CH:68][C:63]=2[N:62]([C:69](NCC2CCN(CC3(C(O)=O)CCOCC3)CC2)=[O:70])[C:61]1=[O:89])([CH3:59])[CH3:58].Cl.[OH-].[Na+]>ClCCl.CO>[CH2:35]([O:42][C:43]([C:45]([CH3:56])([CH3:55])[CH2:46][N:47]1[CH2:52][CH2:51][CH:50]([CH2:53][NH:54][C:69]([N:62]2[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=3[N:60]([CH:57]([CH3:58])[CH3:59])[C:61]2=[O:89])=[O:70])[CH2:49][CH2:48]1)=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(CN1CCC(CN)CC1)C(=O)OCc1ccccc1
Reactant: CC(C)n1c(=O)n(C(=O)NCC2CCN(CC3(C(=O)O)CCOCC3)CC2)c2ccccc21
Agent: CC(C)n1c(=O)[nH]c2ccccc21
Agent: Cl
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CC(C)n1c(=O)n(C(=O)NCC2CCN(CC(C)(C)C(=O)OCc3ccccc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a stirred mixture of 1-isopropyl-1,3-dihydro-2H-benzimidazol-2-one (J. Med. Chem. 1999, 42, 2870-2880) (411 mg, 2.33 mmol) and triethylamine (1.00 mL, 7.17 mmol) in dichloromethane (20.0 mL) was added 4-nitrophenyl chloroformate (470 mg, 2.33 mmol) at room temperature. The resulting mixture was stirred for 2 h at room temperature. To the mixture was added a suspension of 1-(2-benzyloxycarbonyl-2-methylpropyl)-4-aminomethylpiperidine hydrochloride [prepared from concentration of a mixture of tert-butyl [{1-(2-benzyloxycarbonyl-2-methylpropyl)piperidin-4-yl}methyl]carbamate (step 1 of Example 1) (640 mg, 1.49 mmol) and 10% HCl in MeOH (20.0 mL)] and triethylamine (1.00 mL, 7.17 mmol) in dichloromethane (5.00 mL). The resulting mixture was stirred for 13 h at room temperature and 0.5 M NaOH aq. was added to the mixture. The mixture was extracted with dichloromethane. The extracts were washed with 0.5 M NaOH aq. and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (silica gel, eluting with dichloromethane/methanol (10:1)) to give 508 mg (63%) of the title compound as a pale yellow oil.
Reaction SMILES: Br[C:2]1[C:10]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20].C(C([Sn])=C(CCCC)CCCC)CCC.N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=O.[Na+].[O:57]1CCOC[CH2:58]1>C1(C)C=CC=CC=1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O=[Os](=O)(=O)=O>[CH2:12]([O:11][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:5]=[CH:4][C:3]=2[C:2]=1[CH:58]=[O:57])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)c(OCc3ccccc3)ccc21
Reactant: C1COCCO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=[Os](=O)(=O)=O
Agent: CCCCC([Sn])=C(CCCC)CCCC
Solvent: O
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccccc1
Product: O=Cc1c(OCc2ccccc2)ccc2c1ccn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a warm solution of 4-bromo-5-benzyloxy-1-(phenylsulfonyl)-1H-indole (Intermediate 3, 4.74 g, 10.7 mmol) in toluene (100 mL) was added tributylvinyltin (6.80 g, 21.4 mmol) and Pd(PPh3)2Cl2 (0.37 g, 0.50 mmol). The solution was heated at reflux for two hours and more Pd(PPh3)2Cl2 (0.20 g, 0.30 mmol) was added and the reaction mixture was refluxed overnight. A teaspoon of silica gel was added and the mixture was filtered through a pad of silica gel. The solvent was removed under reduced pressure and the resulting oil was triturated with petroleum ether to give a semicrystalline mass (3.6 g) that was dissolved in dioxane (110 mL) and 2,6-lutidine (2.00 g, 18.7 mmol) and OsO4 (0.24 g, 0.94 mmol) were added. The mixture was stirred at room temperature for five minutes. To the dark solution was added a solution of sodium periodate (8.02 g, 37.5 mmol) in water (35 mL) and the resulting suspension was stirred for 30 minutes. More dioxane (40 mL) was added and the mixture was filtered. The filtrate was evaporated to give a dark red oil. The crude product was purified by flash chromatography on silica gel using petroleum ether/EtOAc 90:10 followed by 80:20 as eluent to give the title compound (2.44 g) as a yellow solid. MS m/z 392 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9](Cl)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1>>[N:10]1[C:9]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][CH2:13]2)=[N:8][N:4]2[C:5]([N:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15][CH2:14][CH2:13]3)=[CH:6][CH:7]=[CH:2][C:3]=12
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: c1ccc2c(c1)CCCN2
Product: c1ccc2c(c1)CCCN2c1nc2cccc(N3CCCc4ccccc43)n2n1

Procedure:
1,1′-[1,2,4]triazolo[1,5-a]pyridine-2,5-diyldi-1,2,3,4-tetrahydroquinoline was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (500.0 mg, 2.15 mmol) and 1,2,3,4-tetrahydro-quinoline (274.0 mg, 2.04 mmol) in a manner analogous to Example 2d. Byproduct was isolated as a brown solid (0.033 g, 4%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.14 (d, J=8.2 Hz, 1H), 7.40-7.35 (m, 1H), 7.32-7.28 (m, 1H), 7.15-7.05 (m, 3H), 6.98 (t, J=7.5 Hz, 1H), 6.91-6.84 (m, 2H), 6.69-6.62 (m, 2H), 4.09-4.05 (m, 2H), 3.88-3.83 (m, 2H), 2.93 (t, J=6.4 Hz, 2H), 2.82 (t, J=6.4 Hz, 2H), 2.10-1.80 (m, 4H). MS=382 (MH)+.
Reaction SMILES: [F:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8]([OH:13])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C1(O)C=CC=CC=1.[CH3:21][O:22][C:23](=[O:27])[CH:24](Br)[CH3:25]>>[F:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8]([CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[O:13][CH:24]([CH3:25])[C:23]([O:22][CH3:21])=[O:27]
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1F
Reactant: COC(=O)C(C)Br
Solvent: Oc1ccccc1
Product: COC(=O)C(C)Oc1ccc(C=O)c(F)c1[N+](=O)[O-]

Procedure:
Using 2-fluoro-4-hydroxy-3-nitrobenzaldehyde as the phenol and methyl-2-bromopropanoate as the alkylating agent in the general procedure for alkylation of substituted-2-nitrophenols gives the title compound as a white solid: ESI-MS: m/z 272.1 (M+H)+.
Reaction SMILES: CS[S:3][CH3:4].N(OC(C)(C)C)=O.N[C:13]1[N:17]([CH3:18])[N:16]=[C:15]([C:19]2[C:24]([Cl:25])=[CH:23][C:22]([C:26]([F:29])([F:28])[F:27])=[CH:21][C:20]=2[Cl:30])[C:14]=1[N+:31]([O-:33])=[O:32]>C(Cl)Cl>[Cl:25][C:24]1[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=[C:20]([Cl:30])[C:19]=1[C:15]1[C:14]([N+:31]([O-:33])=[O:32])=[C:13]([S:3][CH3:4])[N:17]([CH3:18])[N:16]=1
Reactant: Cn1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c([N+](=O)[O-])c1N
Reactant: CSSC
Agent: CC(C)(C)ON=O
Solvent: ClCCl
Product: CSc1c([N+](=O)[O-])c(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
First 1.4 g of dimethyl disulfide and then 0.96 g of tert-butyl nitrite were added at 0° C. to a solution of 1.1 g of 5-amino-3-(2,6-dichloro-4-trifluoromethylphenyl)-1-methyl-4-nitropyrazole (14) in 25 ml of anhydrous methylene chloride, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, the resulting residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/1) to afford 0.6 g of the desired compound in the form of a yellow consistent liquid (yield 60.1%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].O.[C:23]1(C)[CH:28]=[CH:27]C=[CH:25][CH:24]=1>>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[N:12][CH:23]([CH2:28][CH3:27])[CH2:24][CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1cccc(Oc2ccccc2)c1
Reactant: Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: CCC(CC)N=Cc1cccc(Oc2ccccc2)c1
Yield: 92.5 %

Procedure:
60.5 g (0.226 mol) of N-3-pentylidene-(3-phenoxybenzylamine is dissolved in 50 ml of toluene; to the solution is then added 2 g (0.0179 mol) of potassium tert-butylate, and the mixture is refluxed for 4 hours. After cooling of the reaction mixture, extraction is effected by shaking with 50 ml of water, and the organic phase is separated in a separating funnel. The toluene is distilled off in a slight water-jet vacuum to leave 56 g (0.21 mol) of 3-phenoxybenzylidene-3-pentylamine, corresponding to a yield of 92.5% of theory; b.p. 125° C./Pa.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH:34]=[CH:33][C:32]5OCO[C:28]=5[CH:27]=4)[CH2:21][CH2:20]3)=[O:18])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH:35]1[C:40]([CH:41]=O)=[CH:39][C:38]2[O:43][CH2:44][O:45][C:37]=2[CH:36]=1.[BH4-].[Na+]>CO>[CH2:25]([N:22]1[CH2:23][CH2:24][N:19]([C:17](=[O:18])[CH2:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][C:5]3[CH:4]=[CH:3][C:2]([NH:1][CH2:41][C:40]4[CH:35]=[CH:36][C:37]5[O:45][CH2:44][O:43][C:38]=5[CH:39]=4)=[CH:7][N:6]=3)=[CH:10][CH:11]=2)[CH2:20][CH2:21]1)[C:26]1[CH:34]=[CH:33][CH:32]=[CH:28][CH:27]=1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: Nc1ccc(Oc2ccc(CCC(=O)N3CCN(Cc4ccc5c(c4)OCO5)CC3)cc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(CCc1ccc(Oc2ccc(NCc3ccc4c(c3)OCO4)cn2)cc1)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-[4-(5-aminopyridin-2-yloxy)phenyl]-1-(4-piperonylpiperazin-1-yl)propane-1-one (1.04 g, 2.5 mmol) was dissolved in methanol (25 mL). To the resulting solution was added piperonal (0.39 g, 2.63 mmol), and this solution was refluxed overnight. The resulting reaction solution was cooled with ice, and then sodium borohydride (0.28 g, 7.50 mmol) was added. The resulting solution was stirred for 2 hours at room temperature. This reaction solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate, and washed with water, saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was then purified by silica gel column chromatography (ethyl acetate), to thereby yield 0.80 g of the title compound.