Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.Cl[C:26]1[N:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[CH:28][N:27]=1>CN1CCCC1=O>[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][N:22]([C:26]3[N:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[CH:28][N:27]=3)[CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:8]=[CH:9][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:11][CH:12]=2)[CH2:4][CH2:3]1
Reactant: CCOc1cnc(Cl)nc1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Agent: Cl
Solvent: CN1CCCC1=O
Product: CCOc1cnc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide hydrochloride and 2-chloro-5-ethoxy-pyrimidine following a procedure analogous to that described in Example 19 using N-methylpyrrolidinone as solvent. LC (method 16): tR=0.46 min; Mass spectrum (ESI+): m/z=434 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][C:12]([O:15][C:16]([NH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:17])([CH3:14])[CH3:13]>CCO>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:22]1[CH2:21][CH2:20][CH:19]([NH:18][C:16](=[O:17])[O:15][C:12]([CH3:13])([CH3:11])[CH3:14])[CH2:24][CH2:23]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(c2ccccc2[N+](=O)[O-])CC1
Yield: 100 %

Procedure:
The method of Example 1 was followed using 1-fluoro-2-nitrobenzene (1.0 eq), 4-N-Boc-aminopiperidine (1.2 eq), and TEA (2.0 eq) in EtOH at 55° C. for 48 hours yielding tert-butyl 1-(2-nitro phenyl)piperidin-4-ylcarbamate (100%). LCMS (m/z): 322.2 (MH+); LC Rt=3.15 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:22]=[C:23]([N:27]=[C:28]=[O:29])[CH:24]=[CH:25][CH:26]=1>>[F:20][C:21]1[CH:22]=[C:23]([NH:27][C:28](=[O:29])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: O=C=Nc1cccc(F)c1
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Product: NC(=O)c1[nH]c2cnccc2c1-c1ccc(NC(=O)Nc2cccc(F)c2)cc1

Procedure:
63 mg of pale yellow solid 3-{4-[3-(3-fluorophenyl)ureido]phenyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and 3-fluorophenyl isocyanate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Li]CCCC.[P:19](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([P:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(Br)cc(OC)c1OC
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(P(c2ccccc2)c2ccccc2)cc(OC)c1OC
Temperature: -78 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a solution of 3,4,5-trimethoxybromobenzene 18 (62.3 g, 0.25 mol) in dry THF (200 ml) was added BuLi solution (169 ml, 1.6M in hexane, 0.27 mol) dropwise at −78° C. within 45 min. The resulting beige-colored suspension was stirred for an additional 1 h at −78° C. Then PPh2Cl (61 g, 0.277 mol, 49.7 ml) was added dropwise. The addition was complete within 2 h. The resulting yellow solution was allowed to warm to 0° C. within 2 h and quenched by addition of NH4Cl solution (200 ml). The organic layer was separated, washed with brine (250 ml), dried (Na2SO4), filtered, and evaporated. The solid was recrystallized from methanol to give 69.5 g(80%) of 19.
Reaction SMILES: [F:1][C:2]1([CH2:26][N:27]=[N+]=[N-])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[F:1][C:2]1([CH2:26][NH2:27])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(F)(CN=[N+]=[N-])CC3)c(F)c2)C(=O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(F)(CN)CC3)c(F)c2)C(=O)O1
Yield: 67 %

Procedure:
The title compound was prepared by reacting (S)-N-{3-[4-(4-fluoro-4-azidomethylpiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (0.73 mmol) with triphenylphosphine (1.27 mmol) in tetrahydrofuran (10 ml) at a temperature 25° C. for six hours and then refluxing for overnight after addition of drop of water followed by purification using silica gel column chromatography in 67% yield.
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:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH2:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1)[CH3:25]>>[CH2:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:1][CH2:2][C@H:3]2[N:8]([C:9]([C:11]3[N:12]=[C:13]([CH3:23])[S:14][C:15]=3[C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)=[O:10])[CH2:7][C@H:6]3[C@@H:4]2[CH2:5]3)=[O:31])=[CH:28][CH:27]=1)[CH3:25]
Reactant: CCc1ccc(C(=O)O)cc1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: CCc1ccc(C(=O)NC[C@@H]2[C@H]3C[C@H]3CN2C(=O)c2nc(C)sc2-c2cccc(C)c2)cc1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 4-Ethyl-benzoic acid.
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)[C:3](=[O:11])[CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[NH4+].[Cl-].O>CO.[Fe]>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([N:2]([CH3:1])[C:3](=[O:11])[CH2:4][N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[CH:13][CH:14]=1
Reactant: CN(C(=O)CN1CCCCC1)c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CN(C(=O)CN1CCCCC1)c1ccc(N)cc1
Yield: 84.4 %

Procedure:
A mixture of 3.12 g (11.3 mmol) of N-Methyl-N-(4-nitrophenyl)-2-piperidin-1-yl-acetamide, 2.52 g (45.1 mmol) of Fe powder and 2.99 g (56.5 mmol) of NH4Cl in 65 mL of MeOH+25 mL of H2O is stirred and refluxed for 3.5 h. The cooled reaction is filtered, the precipitate is washed with MeOH and the filtrate and wash were combined and evaporated. The residue is redissolved in H2O, neutralized with K2CO3 and extracted with EtOAc. The combined extracts were treated with Darco, dried (MgSO4), evaporated and dried in vacuo to give 2.36 g (85%) of brown oil. 1H NMR (DMSO-d6 δ 6.85 (d, 2H, J=7.1 Hz), 6.51 (d, 2H, J=7.1 Hz), 3.30 (s, 2H), 2.78 (s, 3H), 2.24 (s, 4H), 1.50 (m, 6H); MS (ESI) m/z 248.0 (M+H).
Reaction SMILES: Cl.[I:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([C@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1)[CH:8]=[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:6]2=[O:23].C=O.O.[C:27]([BH3-])#N.[Na+]>CO>[I:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([C@H:13]1[CH2:17][CH2:16][N:15]([CH3:27])[CH2:14]1)[CH:8]=[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:6]2=[O:23]
Reactant: CCOC(=O)c1cn([C@H]2CCNC2)c2ccc(I)cc2c1=O
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)c1cn([C@H]2CCN(C)C2)c2ccc(I)cc2c1=O
Temperature: 23 °C
Reaction time: 16 h
Yield: 82.3 %

Procedure:
(S)-Ethyl 6-iodo-4-oxo-1-(pyrrolidin-3-yl)-1,4-dihydroquinoline-3-carboxylate hydrochloride (Intermediate 136, 484 mg, 1.08 mmol) was suspended in methanol (15 mL) then 37% formaldehyde in water (405 μl, 5.4 mmol) and sodium cyanoborohydride (612 mg, 9 7 mmol) were added. The reaction was stirred at 23° C. for 16 h. The volume of the reaction was reduced by half and water (25 mL) was added. The suspension was extracted with 2:1 ethyl acetate: tetrahydrofuran (3×, 10 mL). The organic phases were combined, dried over sodium sulfate, and the solvent was removed in vacuo. The residue was passed through a plug of silica gel (2 g) eluting with 10% methanol in dichloromethane to remove any remaining borohydride. The solid was then dried in a vacuum oven at 50° C. for 18 h to give 379 mg (82% yield) of (S)-ethyl 6-iodo-1-(1-methylpyrrolidin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate as an off white solid.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[C:4]([OH:11])[N:3]=1.S(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+].[O:22]1[CH2:27][CH2:26][NH:25][C:24]2[CH:28]=[N:29][CH:30]=[CH:31][C:23]1=2>>[O:22]1[CH2:27][CH2:26][N:25]([C:8]([C:6]2[CH:5]=[C:4]([OH:11])[N:3]=[C:2]([OH:1])[N:7]=2)=[O:10])[C:24]2[CH:28]=[N:29][CH:30]=[CH:31][C:23]1=2
Reactant: c1cc2c(cn1)NCCO2
Reactant: O=C(O)c1cc(O)nc(O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Product: O=C(c1cc(O)nc(O)n1)N1CCOc2ccncc21

Procedure:
By the same method as in Example 59, 2,6-dihydroxy-pyrimidin-4-carboxylic acid (125 mg, 0.80 mmol), thionyl chloride (0.066 ml, 0.90 mmol), potassium carbonate (138 mg, 1.0 mmol) and 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (109 mg, 0.80 mmol) were reacted and the reaction mixture was purified in the same manner to obtain the target compound 60, i.e., (2,3-dihydro-pyrido[4,3-b][1,4]oxazin-4-yl)-(2,6-dihydroxy-pyrimidin-4-yl)-methanone, as white solid (32 mg, 15%).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.FC(F)(F)C([O-])=O.[C:32]([C:35]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:40][CH2:39][NH2+:38][CH2:37][CH2:36]1)(=[O:34])[NH2:33].C(N(CC)CC)C>C(O)C>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:5]1[N:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:7]2[C:3]([N:4]=1)=[C:2]([N:38]1[CH2:37][CH2:36][C:35]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)([C:32]([NH2:33])=[O:34])[CH2:40][CH2:39]1)[N:10]=[CH:9][N:8]=2
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(Cl)ncnc32)cc1
Reactant: NC(=O)C1(c2ccccc2)CC[NH2+]CC1
Agent: O=C([O-])C(F)(F)F
Solvent: CCO
Solvent: CCN(CC)CC
Product: NC(=O)C1(c2ccccc2)CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Temperature: 55 °C
Yield: 62.3 %

Procedure:
To a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purine (23.1 mg, 0.062 mmol, 1 eq.) in 2 mL of ethanol was added 4-carbamoyl-4-phenylpiperidin-1-ium trifluoroacetate (25 mg, 0.123 mmol, 2 eq.) and triethylamine (0.03 mL, 0.19 mmol, 3 eq.). The reaction was heated to 55° C. for 3 d. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 21 mg (63%) of 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]-4-phenylpiperidine-4-carboxamide. 1H NMR (300 MHz, METHANOL-d4) δ ppm 2.02-2.21 (m, 2 H) 2.62 (d, J=13.37 Hz, 2 H) 3.82 (br. s., 2H) 4.98 (d, J=15.54 Hz, 2H) 7.07-7.67 (m, 13 H) 8.02-8.29 (m, 1 H), [M+H]+ 543.6.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[C:3]([CH:4]=[O:5])=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=Cc1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=Cc1ccccc1-c1ccc(Cl)cc1

Procedure:
2-bromobenzaldehyde (25.05 mL, 40.0 g, 216 mmol) was added to toluene (550 mL) and degassed and flushed with nitrogen. 4-chlorophenylboronic acid (43.9 g, 281 mmol), degassed 2M sodium carbonate (757 mL, 1513 mmol), and tetrakis(triphenylphosphine)palladium(0) (5.00 g, 4.32 mmol) were added. The mixture was refluxed for 2.5 hours, cooled, and the phases were separated. The organic layer was extracted with 2M sodium carbonate, and the aqueous layer was back extracted with ethyl ether. The organic portions were combined, dried with brine and then anhydrous sodium sulfate. The solution was concentrated and purified by flash column chromatography on silica gel with 3% ethyl acetate (in hexanes) increasing to 10% ethyl acetate (in hexanes).
Reaction SMILES: [C:1](=O)([O:43]C1C=CC([N+]([O-])=O)=CC=1)[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([NH:31][C:32]([O:34][C@@H:35]2[C@H:42]3[C@H:38]([O:39][CH2:40][CH2:41]3)[O:37][CH2:36]2)=[O:33])[C@H:11]([OH:30])[CH2:12][N:13]([S:18]([C:21]2[CH:29]=[CH:28][C:24]3[O:25][CH2:26][O:27][C:23]=3[CH:22]=2)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:5][CH:4]=1.[OH-].[NH4+:55]>>[NH2:55][C:1]([O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([NH:31][C:32](=[O:33])[O:34][C@@H:35]2[C@H:42]3[C@H:38]([O:39][CH2:40][CH2:41]3)[O:37][CH2:36]2)[C@H:11]([OH:30])[CH2:12][N:13]([S:18]([C:21]2[CH:29]=[CH:28][C:24]3[O:25][CH2:26][O:27][C:23]=3[CH:22]=2)(=[O:19])=[O:20])[CH2:14][CH:15]([CH3:16])[CH3:17])=[CH:5][CH:4]=1)=[O:43]
Reactant: [NH4+]
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Agent: [OH-]
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OC(N)=O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2

Procedure:
4-{(2S,3R)-2-({[(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl}amino)-4-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-3-hydroxybutyl}phenyl 4-nitrophenyl carbonate was treated with concentrated ammonium hydroxide as described in Example 311 to afford the title compound as a white solid. 1H NMR (DMSO-d6): δ 0.78 (3H, d), 0.86 (3H, d), 1.2 (1H, dd), 1.4 (1H, br quintuplet), 1.85-1.95 (1H, m), 2.2 (1H, t), 2.65-2.80 (3H, m), 2.9-3.0 (2H, m), 3.25-3.30 (1H, m), 3.5-3.6 (4H, m), 3.7 (1H, t), 3.8 (1H, dd), 4.8 (1H, dt), 5.0 (1H, d), 5.4 (1H, d), 6.18 (2H, d), 6.8 (2H, br d), 6.9 (2H, d), 7.0 (1H, d), 7.15 (2H, d), 7.2 (1H, s), 7.25-7.30 (2H, m); MS: 636 (MH+).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([NH:22][C:23](=[O:25])[CH3:24])[CH:19]=[N:18]2)=[CH:13][CH:12]=1.[H-].[Na+].I[CH3:29]>O1CCCC1.O>[CH3:29][N:22]([C:20]1[CH:19]=[N:18][N:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:3]3[CH2:4][CH2:5][CH2:6][C@H:2]3[CH3:1])=[CH:12][CH:13]=2)[CH:21]=1)[C:23](=[O:25])[CH3:24]
Reactant: CC(=O)Nc1cnn(-c2ccc(OCCCN3CCC[C@H]3C)cc2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N(C)c1cnn(-c2ccc(OCCCN3CCC[C@H]3C)cc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.8 %

Procedure:
To a solution of N-[1-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1H-pyrazol-4-yl]acetamide obtained in Example 37 (0.34 g) in tetrahydrofuran (3.5 mL), sodium hydride (55% in mineral oil, 0.048 g) was added and iodomethane (0.225 g) was then added dropwise under ice cooling, followed by stirring at room temperature for 1.5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: ethyl acetate:hexane=1:1→ethyl acetate), and the resulting crystal was washed with diisopropyl ether to give the titled compound (0.187 g) as a white solid.
Reaction SMILES: [CH2:1]([N:5]([CH2:35][CH2:36][CH2:37][CH3:38])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([N:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])[NH:11][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[C:39]([O:43][C:44](=[O:47])[CH2:45]Br)([CH3:42])([CH3:41])[CH3:40]>>[C:39]([O:43][C:44](=[O:47])[CH2:45][N:11]1[CH:12]=[C:8]([C:6](=[O:7])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:35][CH2:36][CH2:37][CH3:38])[N:9]=[C:10]1[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[C:23]([N:25]1[CH2:34][CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26]1)=[O:24])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCCCN(CCCC)C(=O)c1c[nH]c(-c2ccc(C(=O)OC)cc2C(=O)N2CCc3ccccc3C2)n1
Product: CCCCN(CCCC)C(=O)c1cn(CC(=O)OC(C)(C)C)c(-c2ccc(C(=O)OC)cc2C(=O)N2CCc3ccccc3C2)n1
Yield: 79.3 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 264K, methyl 4-(4-(dibutylcarbamoyl)-1H-imidazol-2-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (310 mg, 0.6 mmol) and t-butylbromoacetate (117 mg, 0.6 mmol) were converted to the title compound (300 mg, 90%). MS(ESI+) m/z 631.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:10][C:9]2[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=2[NH:7][C:6]1=[O:24])=[O:4].C[Si](C)(C)[N-][Si](C)(C)C.[K+].C1(C)C=CC=CC=1.[O:42]=O>O1CCCC1>[OH:42][C:5]1([C:3]([O:2][CH3:1])=[O:4])[CH:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[CH2:10][C:9]2[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=2[NH:7][C:6]1=[O:24]
Reactant: O=O
Reactant: COC(=O)C1C(=O)Nc2ccccc2CC1c1ccc(OC)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)C1(O)C(=O)Nc2ccccc2CC1c1ccc(OC)cc1
Reaction time: 2.5 h

Procedure:
Dry oxygen gas was bubbled through a cooled (ice bath) solution of 1,3,4,5-tetrahydro-3-(methoxycarbonyl)-4-(4-methoxyphenyl)-2H-1-benzazepin-2-one (13 g, 40.2 mmol) in 130 ml of dry tetrahydrofuran for 30 minutes. Potassium hexamethyldisilazide in toluene (180 ml, 0.67M, 120.5 mmol) was then added over a 7 minute period under a continuous stream of oxygen. After stirring for 2.5 hours, the oxygen flow was terminated and the reaction was quenched by the addition of 200 ml of 5% potassium bisulfate. Solid sodium sulfite (15 g) was then added followed by the addition of 100 ml of methanol and the mixture was stirred for an additional 30 minutes. The mixture was then extracted twice with ethyl acetate and the combined organic layers were washed three times with 1M hydrochloric acid, once with saturated bicarbonate solution followed by brine and then dried over sodium sulfate. Concentration afforded 15 g of crude product which was triturated with ether-hexane to yield 9.3 g of high purity product.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([CH:29]1[CH2:32][CH:31]([CH:33]=O)[CH2:30]1)[CH:26]([CH3:28])[CH3:27].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:33][CH:31]1[CH2:32][CH:29]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:30]1
Reactant: CC(C)CC1CC(C=O)C1
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)CC1CC(C=C(Br)Br)C1
Reaction time: 0.33 h

Procedure:
To a solution of carbon tetrabromide (168 g) in methylene chloride (252 mL) was added dropwise a solution of triphenylphosphine (266 g) in methylene chloride (350 mL) at ice temperature. The mixture was stirred at ice temperature for 20 min. To the mixture was then added dropwise a solution of 3-isobutylcyclobutanecarbaldehyde in methylene chloride at ice temperature. The mixture was stirred at ice temperature for 20 min. After an addition of aqueous 10 w/v % sodium carbonate (1 L) dropwise to the mixture, the mixture was extracted with methylene chloride (200 mL×2). The combined organic layer was washed with water and brine, then dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo. To the resultant residue were added hexane/chloroform=1/1 (750 mL), silica gel (750 mL) and hexane (900 mL). The mixture was filtered and the filtrate was concentrated in vacuo. To the resultant residue was added hexane (500 mL). The mixture was filtered and the filtrate was concentrated in vacuo. The resultant residue was purified by silica gel column chromatography (Eluent: hexane) to give the title compound (76.21 g).
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19](=[O:20])[CH2:18][CH2:17][C@H:16]2[C:21](=[O:32])[NH:22][C:23]2[CH:27]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[O:25][N:24]=2)=[CH:11][CH:10]=1)C)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:28]([C:26]1[O:25][N:24]=[C:23]([NH:22][C:21]([C@@H:16]2[CH2:17][CH2:18][C:19](=[O:20])[N:15]2[C:12]2[CH:13]=[CH:14][C:9]([NH:7][CH3:6])=[CH:10][CH:11]=2)=[O:32])[CH:27]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(N2C(=O)CC[C@H]2C(=O)Nc2cc(C(C)(C)C)on2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1ccc(N2C(=O)CC[C@H]2C(=O)Nc2cc(C(C)(C)C)on2)cc1

Procedure:
A solution of {4-[(S)-2-(5-tert-butyl-isoxazol-3-ylcarbamoyl)-5-oxo-pyrrolidin-1-yl]-phenyl}-methyl-carbamic acid tert-butyl ester (550 mg, 1.21 mmol) in dichloromethane (5 mL) is cooled in an ice bath. A pre-cooled trifluoroacetic acid (15 mL) is added and the mixture is kept in ice-bath for 30 minutes. Trifluoroacetic acid is evaporated in vacuo, and the residue is treated with ice and sodium bicarbonate solution. Extracted with ethyl acetate (1×150 mL) and the combined extracts washed with brine (50 mL) dried over anhydrous Na2SO4 and solvent removed in vacuo to give the title compound, ESI m/z 357 [M+H]+.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH2:9]O)[CH2:5][CH2:4][CH2:3][CH2:2]1.P(Br)(Br)[Br:15]>C(Cl)Cl>[CH:1]1([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH2:9][Br:15])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCc1cccc(C2CCCC2)c1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: BrCc1cccc(C2CCCC2)c1
Yield: 100 %

Procedure:
According to example 17, 5.77 g of 3-cyclopentylbenzyl alcohol was treated with 1.09 mL of PBr3 in 25 mL of anhydrous CH2Cl2 to afford 7.85 g (100%) of 3-cyclopentylbenzyl bromide as a light yellow liquid.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[C:24]([OH:28])(=O)[CH2:25][CH3:26].[NH2:29][CH2:30][CH2:31][CH:32]1[C:44]2[C:43]3[NH:42][C:41](=[O:45])[CH2:40][O:39][C:38]=3[CH:37]=[CH:36][C:35]=2[CH2:34][CH2:33]1>CN(C)C=O.O>[O:45]=[C:41]1[CH2:40][O:39][C:38]2[CH:37]=[CH:36][C:35]3[CH2:34][CH2:33][CH:32]([CH2:31][CH2:30][NH:29][C:24](=[O:28])[CH2:25][CH3:26])[C:44]=3[C:43]=2[NH:42]1
Reactant: CCC(=O)O
Reactant: NCCC1CCc2ccc3c(c21)NC(=O)CO3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCC(=O)NCCC1CCc2ccc3c(c21)NC(=O)CO3
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (372.0 mg, 1.9 mmol.) and 1-hydroxybenzotriazole monohydrate (257 mg, 1.9 mmol.) were suspended in N,N-dimethylformamide (2.5 mL). To the suspension was added, under ice-cooling, propionic acid (0.11 mL, 1.4 mmol.). This reaction mixture was stirred for one hour at room temperature, and, then, cooled again with ice, to which was added dropwise a solution of 9-(2-aminoethyl)-1,7,8,9-tetrahydroindeno[5,4-b][1,4] oxazin-2(3H)-one (300 mg, 1.3 mmol.) in N,N-dimethylformamide (1.5 mL). The mixture was stirred for one hour under ice-cooling. The reaction mixture was poured into water, and the organic matter was extracted with ethyl acetate. The extract solution was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by means of silica gel column chromatography (chloroform:methanol=10:1) to afford the title compound (yield 253.0 mg, 88%).