Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[NH:18][C:17]4[CH:19]=[CH:20][C:21]([C:23]#[N:24])=[CH:22][C:16]=4[N:15]=3)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>N1C=CC=CC=1>[N:25]1([C:2]2[C:3]([N:8]3[CH2:9][CH2:10][CH:11]([C:14]4[NH:18][C:17]5[CH:19]=[CH:20][C:21]([C:23]#[N:24])=[CH:22][C:16]=5[N:15]=4)[CH2:12][CH2:13]3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: C1COCCN1
Reactant: N#Cc1ccc2[nH]c(C3CCN(c4nccnc4Cl)CC3)nc2c1
Solvent: c1ccncc1
Product: N#Cc1ccc2[nH]c(C3CCN(c4nccnc4N4CCOCC4)CC3)nc2c1
Temperature: 130 °C
Yield: 16 %

Procedure:
A mixture of 2-[1-(3-chloro-pyrazin-2-yl)-piperidin-4-yl]-1H-benzoimidazole-5-carbonitrile (150 mg, 0.68 mmol) and morpholine (3 mL) in pyridine was heated at 130° C. under microwave for 45 min. Then it was concentrated to give the crude product which was purified by column chromatography and followed by preparative HPLC to afford pure product 2-[1-(3-morpholin-4-yl-pyrazin-2-yl)-piperidin-4-yl]-1H-benzoimidazole-5-carbonitrile (30 mg, 16%). [M+1] 390. IC50 (uM) 1.996.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:11]1[N:12]([CH2:33][CH:34]2[CH2:36][CH2:35]2)[C:13]2[C:18]([N:19]=1)=[C:17]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[N:16]=[C:15]([C:26]1[CH:27]=[N:28][C:29]([NH2:32])=[N:30][CH:31]=1)[N:14]=2>CS(C)=O>[NH2:32][C:29]1[N:28]=[CH:27][C:26]([C:15]2[N:14]=[C:13]3[C:18]([N:19]=[C:11]([NH:9][CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[N:12]3[CH2:33][CH:34]3[CH2:36][CH2:35]3)=[C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:16]=2)=[CH:31][N:30]=1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CC4)c3n2)cn1
Reactant: NCCN1CCOCC1
Solvent: CS(C)=O
Product: Nc1ncc(-c2nc(N3CCOCC3)c3nc(NCCN4CCOCC4)n(CC4CC4)c3n2)cn1
Temperature: 150 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
2-Morpholin-4-yl-ethylamine (168 mg, 1.29 mmol) and dimethyl sulfoxide (1 ml) were added to 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]pyrimidin-2-amine (100 mg, 0.26 mmol) and the resulting mixture was stirred at 150° C. for 4 hours. The reaction mixture was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (85 mg, 62%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:28])[C:15](=[O:27])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([SH:26])[CH:17]=2)=[C:4]([O:29][CH3:30])[CH:3]=1.I[CH:32]1[CH2:35][O:34][CH2:33]1.CCN(C(C)C)C(C)C.[NH4+].[Cl-]>C(#N)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:28])[C:15](=[O:27])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([S:26][CH:32]3[CH2:35][O:34][CH2:33]3)[CH:17]=2)=[C:4]([O:29][CH3:30])[CH:3]=1
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(S)cc(C(F)(F)F)c1
Reactant: IC1COC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(SC2COC2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of N-(4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)-3-mercapto-N-methyl-5-(trifluoromethyl)benzamide (0.1 g, 229 μmol, example 129, intermediate) in acetonitrile (2 mL) were added 3-iodooxetane (52.7 mg, 286 μmol, CAS RN 26272-85-5) and DIPEA (74.0 mg, 100 μL, 573 μmol) and the yellow solution was stirred at room temperature for 1.5 hours. Then heating was installed and the yellow solution was stirred at reflux for 2.5 hours. The colorless solution was poured on saturated aqueous NH4Cl solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were dried over MgSO4, filtered, and evaporated. The compound was purified by silica gel chromatography on a 10 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light brown foam (0.052 g; 46%). MS (ESI): m/z=493.12 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.CON(C)[C:16](=[O:23])[CH2:17][C:18]1[CH:22]=[CH:21][S:20][CH:19]=1.[NH4+].[Cl-]>C1COCC1>[C:2]1([C:16](=[O:23])[CH2:17][C:18]2[CH:22]=[CH:21][S:20][CH:19]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: CON(C)C(=O)Cc1ccsc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(Cc1ccsc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 54.9 %

Procedure:
To the solution of bromo-benzene (1.0 g, 6.36 mmol) in anhydrous THF (30 mL) was added n-BuLi (5.9 mmol, 2.4 mL) at −78° C. under nitrogen, and the mixture was stirred at −78° C. for further 20 min., a solution of N-methoxy-N-methyl-2-(thiophen-3-yl)acetamide (1 g, 5.4 mmol) in anhydrous THF (10 mL) was added. The resulting mixture was stirred at −78° C. under nitrogen for about 30 min., poured into NH4Cl aqueous solution, and extracted with EtOAc. The organic layers were washed with brine, dried over sodium sulfate, concentrated, and purified by column chromatograph (PE:EtOAc=20:1) to afford Intermediate 2 as a colorless oil (600 mg, yield 55.0%).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[N:27]1([C:34]2[N:38]([CH3:39])[C:37]3[CH:40]=[CH:41][CH:42]=[CH:43][C:36]=3[N:35]=2)[CH2:33][CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:30]2[CH2:31][CH2:32][CH2:33][N:27]([C:34]3[N:38]([CH3:39])[C:37]4[CH:40]=[CH:41][CH:42]=[CH:43][C:36]=4[N:35]=3)[CH2:28][CH2:29]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: Cn1c(N2CCCNCC2)nc2ccccc21
Product: Cn1c(N2CCCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)nc2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-[1.4]diazepan-1-yl-1-methyl-1H-benzimidazole.
Reaction SMILES: [CH:1]([Mg]Br)([CH3:3])[CH3:2].C(OCC)C.[CH:11]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17])=[O:12]>O1CCCC1>[OH:12][CH:11]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17])[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)[Mg]Br
Reactant: N#Cc1cccc(C=O)c1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)C(O)c1cccc(C#N)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
15% Isopropyl magnesium bromide in diethyl ether (23.5 mL, 24.0 mmol) was added to a stirred solution of 3-formylbenzonitrile (2.62 mg, 20.0 mmol) in dry tetrahydrofuran (18 mL), at 0° C. under a nitrogen atmosphere. After stirring at 0° C. for 1 hour, then at room temperature for 2 hours, the mixture was partitioned between ethyl acetate and 1M hydrochloric acid. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified with silica column chromatography (eluting with 9% to 25% ethyl acetate in heptane) to afford the title compound (1.164 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]1[C:10](=[O:11])[NH:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[O:6]1.NC1C=CC=CC=1O.BrC(CCCBr)C(Br)=O.[CH2:33]([CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.Cl>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH2:33]([CH:40]1[CH2:45][CH2:44][N:43]([CH2:2][CH2:3][CH2:4][CH:5]2[C:10](=[O:11])[NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[O:6]2)[CH2:42][CH2:41]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C1Nc2ccccc2OC1CCCBr
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: Cl
Agent: Nc1ccccc1O
Agent: O=C(Br)C(Br)CCCBr
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C1Nc2ccccc2OC1CCCN1CCC(Cc2ccccc2)CC1

Procedure:
5.6 g (=0.02 m) of 2-(3-bromopropyl)-2H-1,4-benzoxazine-3(4H)-one prepared analogously to Example 1B starting from 2-aminophenol and 2,5-dibromopentanoyl bromide, 3.86 g (=0.022 m) of 4-benzylpiperidine, and 4.05 g of triethylamine were successively introduced into 70 ml of toluene. The reaction mixture was heated at reflux for 7 hours with stirring. To work up the reaction mixture it was cooled, and 100 ml of aqueous 20% strength hydrochloric acid solution were added. An oily paste was formed which was separated, washed with toluene, and then suspended in a mixture of aqueous sodium bicarbonate solution and dichloromethane. The organic phase was separated, dried over sodium sulfate, and then the solvent was distilled off. The remaining oily residue was fractionated by column chromatography. The title compound obtained in this way was crystallized from 15 ml of ethyl acetate. 6 g of 2-[3-(4-benzylpiperidin-1-yl)-propyl]-2H-1,4-benzoxazine-3(4H)-one were obtained as white crystals having a melting point of 108° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH2:15]([C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.ClCCl.CO>[CH2:15]([C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([NH:14][CH2:13][CH2:12][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([Cl:2])[CH:4]=2)[NH:8][CH:7]=1)=[O:25])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)c1ccccc1Cc1ccccc1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1Cc1ccccc1
Yield: 39.4 %

Procedure:
2-Benzyl-N-(2-(5-chloro-1H-indol-3-yl)ethyl)benzamide was prepared following Method A starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.424 mmol), 2-benzylbenzoic acid (0.102 g; 0.466 mmol), HATU (0.177 g; 0.466 mmol) and N,N-diisopropylethylamine (0.179 mL; 1.06 mmol) in DMF (5 mL). Flash chromatography on silica gel eluting with 1 to 10% methanol in dichloromethane furnished 0.065 g (40%) of 2-benzyl-N-(2-(5-chloro-1H-indol-3-yl)ethyl)benzamide as a white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]([C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]2[N:32]=[CH:31][C:30]([C:33](O)=[O:34])=[CH:29][CH:28]=2)=[O:26])=[CH:20][CH:19]=1)([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12].O1CCOCC1.[CH3:42][NH2:43]>C(Cl)Cl.CN(C=O)C.O>[F:7][C:8]([C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:25]([C:27]2[CH:28]=[CH:29][C:30]([C:33](=[O:34])[NH:43][CH3:42])=[CH:31][N:32]=2)=[O:26])=[CH:22][CH:23]=1)([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:12])=[O:13]
Reactant: CN
Reactant: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(NC(=O)c2ccc(C(=O)O)cn2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1ccc(C(=O)Nc2ccc(C(C)(F)CNS(=O)(=O)C(C)C)cc2)nc1
Temperature: 25 °C
Yield: 25 %

Procedure:
Into a 50 mL single neck flask, 1 mL oxalyl chloride was added syringe wise to 6-{N-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]carbamoyl}pyridine-3-carboxylic acid. (110 mg, 0.26 mmol, prepared in example 51) in methylene chloride (10 mL) while stirring under nitrogen at room temperature. Immediately, 1 drop of DMF was added by pipette initiating a foaming of the mixture. The reaction was stirred one hour at this temperature and then concentrated under reduced vacuum to yield a white semi-solid. This material was placed into dioxane (10 mL) and added dropwise to a stirring solution of 40% methylamine in water (3 mL, excess) at room temperature and the mixture was stirred overnight. In the morning, the solution was concentrated under reduced vacuum and the resulting oil was taken into methylene chloride and the organic layer was washed once with H2O, dried over K2CO3, filtered, and concentrated under reduced vacuum to yield 78 mg as an oil. This material was purified via silica gel chromatography employing the chromatotron and using a 1000 micron rotor while eluting with a solvent of ethyl acetate to yield the title compound (28 mg, 25%) as a white solid. Ion spray M.S. 435.2 (M*−1) and 417.1 (M*−19 Fluorine).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:22]=[CH:21][C:8]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[C:12]=2[CH3:20])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:4][C:5]1[CH:22]=[CH:21][C:8]([CH2:9][N:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[C:12]=2[CH3:20])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(CNc2cccc([N+](=O)[O-])c2C)cc1
Reactant: BrCc1ccccc1
Product: C=CCOc1ccc(CN(Cc2ccccc2)c2cccc([N+](=O)[O-])c2C)cc1

Procedure:
The product from Example 19A and benzyl bromide were processed as described in Example 6B to provide the title compound. MS (ESI+) m/z 389 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][N:5]([CH3:21])[C:6]1[CH:11]=[CH:10][C:9]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)=[CH:8][CH:7]=1.I[C:24]1C=CC(N2CC[C@@H](N(C)C)C2)=CC=1>>[CH3:1][N:2]([CH3:22])[C@@H:3]1[CH2:24][CH2:21][N:5]([C:6]2[CH:7]=[CH:8][C:9]([B:12]3[O:16][C:15]([CH3:17])([CH3:18])[C:14]([CH3:20])([CH3:19])[O:13]3)=[CH:10][CH:11]=2)[CH2:4]1
Reactant: CN(C)CCN(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CN(C)[C@@H]1CCN(c2ccc(I)cc2)C1
Product: CN(C)[C@@H]1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C1

Procedure:
The title compound was synthesized according to the synthesis of N,N,N′-trimethyl-N′-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethane-1,2-diamine, substituting (R)-1-(4-iodophenyl)-N,N-dimethylpyrrolidin-3-amine (300 mg, 0.95 mmol). The title compound was purified by silica gel chromatography (MeOH/CH2Cl2, 2:98 to 12:88) as a yellow solid (95 mg, 32%). 1H NMR (400 MHz, MeOD) δ 7.58 (d, J=7.6 Hz, 2H), 6.52 (d, J=7.8 Hz, 2H), 3.55-3.51 (m, 1H), 3.48-3.43 (m, 1H), 3.32-3.26 (m, 1H), 3.15-3.11 (m, 1H), 2.92-2.86 (m, 1H), 2.55 (s, 3H), 2.32 (s, 6H), 2.28-2.22 (m, 1H), 1.94-1.86 (m, 1H); MS ESI 317.2 [M+H]+, calcd for [C18H29BN2O2+H]+ 317.23.
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:8]=1[C:9](Cl)=[O:10].[F:17][C:18]([F:32])([F:31])[CH2:19][O:20][C:21]1[CH:30]=[CH:29][C:24]([O:25][CH2:26][CH2:27][NH2:28])=[CH:23][CH:22]=1>C(N(CC)CC)C>[F:17][C:18]([F:31])([F:32])[CH2:19][O:20][C:21]1[CH:30]=[CH:29][C:24]([O:25][CH2:26][CH2:27][NH:28][C:9](=[O:10])[C:8]2[C:7]([F:6])=[CH:15][CH:14]=[CH:13][C:12]=2[F:16])=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: NCCOc1ccc(OCC(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCCOc1ccc(OCC(F)(F)F)cc1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A tetrahydrofuran (5 ml) solution of 2,6-difluorobenzoyl chloride (0.70 g) was added dropwise under ice-cooling and stirring to a tetrahydrofuran (20 ml) solution of 2-[4-(2,2,2-trifluoroethoxy)phenoxy]ethylamine (0.94 g) and triethylamine (0.40 g) and the mixture was further stirred at room temperature for one hour.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:20].S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][N+:3]=1[O-:20]
Reactant: Cc1ccc(Oc2ccccc2)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(Oc2ccccc2)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 86.3 %

Procedure:
A mixture of 2-methyl-5-phenoxy-pyridine (3.6 g, 19 mmol) described in Manufacturing Example 121-1-1, 3-chloroperoxybenzoic acid (5.6 g, 33 mmol), and methylene chloride (80 mL) was stirred at room temperature for 45 minutes. Aqueous sodium sulfite was added to the reaction solution, and the organic layer was separated and was washed with 5 N aqueous sodium hydroxide (7 mL). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under a reduced pressure to obtain 2-methyl-5-phenoxy-pyridine 1-oxide (3.3 g). 2-methyl-5-phenoxy-pyridine 1-oxide (3.3 g, 16 mmol) and acetic anhydride (20 mL) were stirred for 40 minutes at 115° C. Acetic anhydride was evaporated under a reduced pressure, aqueous sodium bicarbonate and ethyl acetate were added to the residue, and the organic layer was separated. The ethyl acetate solution was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain an acetic acid 5-phenoxy-pyridin-2-ylmethyl ester (3.0 g). Acetic acid 5-phenoxy-pyridin-2-ylmethyl ester (3.0 g, 12 mmol), 5 N aqueous sodium hydroxide (8.0 mL), and methanol (20 mL) were stirred for 20 minutes at 60° C. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under a reduced pressure to obtain the title compound (2.6 g, 65%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[S:8])[NH2:7].Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O>C(O)C.O>[C:13]1([C:11]2[N:7]=[C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[S:8][CH:10]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NC(=S)c1cccs1
Reactant: O=C(CBr)c1ccccc1
Solvent: CCO
Solvent: O
Product: c1ccc(-c2csc(-c3cccs3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.5 %

Procedure:
To a stirred solution of 2-thiophenethiocarboxamide (1.56 g, 0.0109 mole) in ethanol (50 mL) was added 2-bromoacetophenone (2.19 g, 0.0110 mole). After complete addition the mixture was heated at reflux for two hours, then was allowed to cool to room temperature and stir for approximately 18 hours. The solvent was removed from the reaction mixture by evaporation under reduced pressure, leaving an oil which solidified. This solid was suspended in water and extracted twice with methylene chloride. The extracts were combined, dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 2.48 g of 4-phenyl-2-(thien-2-yl)thiazole as a solid, mp 51°-53° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH:15]2[CH:24]([OH:25])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([OH:26])[CH:22]=3)[O:17][CH2:16]2)[CH:9]=1>>[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][C@H:15]2[C@@H:24]([OH:25])[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:26][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=4)[CH:22]=3)[O:17][CH2:16]2)[CH:9]=1
Reactant: Clc1ccccn1
Reactant: Oc1ccc2c(c1)C(O)C(Cc1cccnc1)CO2
Product: O[C@H]1c2cc(Oc3ccccn3)ccc2OC[C@H]1Cc1cccnc1

Procedure:
By the method of Example 1, 2-chloropyridine and 3-(3-pyridylmethyl)-4,6-chromandiol were converted to present title product in like yield; mp 67°-68° C.; IR(CHCl3) 1598; 1491 cm-1.
Reaction SMILES: CON(C)[C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([N:12]2[CH:16]=[CH:15][CH:14]=[CH:13]2)[CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([CH:4]=[O:17])=[CH:6][C:7]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1
Reactant: CON(C)C(=O)c1ccc(Cl)c(-n2cccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1ccc(Cl)c(-n2cccc2)c1
Temperature: 2.5 °C
Reaction time: 0.75 h
Yield: 72.1 %

Procedure:
A solution of 1.5 g of N-methoxy-N-methyl-4-chloro-3-(1H-pyrrol-1-yl)benzamide in 30 ml of anhydrous tetrahydrofuran was added drop-wise over a period of 30 minutes to a solution, pre-cooled to 0-5° C., of 237 mg of lithium aluminium hydride (98%) in 30 ml of anhydrous tetrahydrofuran. The mixture was stirred at 0-5° C. for a further 45 minutes and ther reaction was then quenched by the adition of 25 ml of saturated aqueous ammonium chloride solution and 25 ml of 50% aqueous hydrochloric acid. The mixture was then extracted with three 100 ml portions of diethyl ether and the combined extracts were dried over anhydrous magnesium sulphate. The solvents were removed under reduced pressure and the residue was purified by column chromatography on silica gel using hexane/ethyl acetate (90:10) as the eluent to give 0.84 g of 4-chloro-3-(1H-pyrrol-1-yl)benzaldehyde as a yellow oil; nmr (CDCl3,250 Mhz) dH 10.00 (CHO).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27](OCC)=[O:28])=[CH:21][CH:20]=1.[Li+].CC([N-]C(C)C)C>>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:26]([CH2:25][C:22]3[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=3)[C:27]2=[O:28])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CCc1ccncc1
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: O=c1c(Cc2ccncc2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 3-(pyridin-4-yl)propionate (1.1 eq.) and LDA (1.5 eq.) to obtain a product which was subjected to recrystallization from ethyl acetate-methanol to give 1-(3-nitrophenyl)-3-(pyridin-4-ylmethyl)-1,8-naphthyridin-2(1H)-one as a pale brown powder, mp 230° C./EtOAc-MeOH (decomp.).
Reaction SMILES: C([O:8][CH:9]1[CH:13]([NH:14][C:15]([CH:17]2[N:22]3[C:23](=[O:40])[CH:24]([NH:29][C:30](=[O:39])[CH2:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:25][CH2:26][C:27](=[O:28])[N:21]3[CH2:20][CH2:19][CH2:18]2)=[O:16])[CH2:12][C:11](=[O:41])[O:10]1)C1C=CC=CC=1>[Pd].CO>[O:28]=[C:27]1[CH2:26][CH2:25][CH:24]([NH:29][C:30](=[O:39])[CH2:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:23](=[O:40])[N:22]2[CH:17]([C:15]([NH:14][CH:13]([CH:9]=[O:8])[CH2:12][C:11]([OH:41])=[O:10])=[O:16])[CH2:18][CH2:19][CH2:20][N:21]12
Reactant: O=C(CCc1ccccc1)NC1CCC(=O)N2CCCC(C(=O)NC3CC(=O)OC3OCc3ccccc3)N2C1=O
Agent: [Pd]
Solvent: CO
Product: O=CC(CC(=O)O)NC(=O)C1CCCN2C(=O)CCC(NC(=O)CCc3ccccc3)C(=O)N12
Reaction time: 5 h

Procedure:
A mixture of [3S,2R,S, (1S,9S)] N-(2-benzyloxy-5-oxotetrahydrofuran-3-yl)-6,10-dioxo-octahydro-9-(3-phenylpropionylamino)-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxamide (46a) (205 mg; 0.364 mmol), 10% palladium on carbon (200 mg) and methanol (20 ml) was stirred under hydrogen at atmospheric pressure for 5 h. The mixture was filtered then concentrated to yeild 154 mg (90%) of a glass: mp. 116-118° C.; [α]D23 −140° (c 0.1, CH3OH); IR (KBr) 3323 (br), 1783, 1731, 1658, 1539, 1455, 1425; 1H NMR (CD3OD) δ7.21 (5H, m), 5.17 (1H, m), 4.73 (1H, m), 4.50 (2H, m), 4.23 (1H, m), 3.38 (1H, m), 3.06 (1H, m), 2.91 (2H, m), 2.73-2.18 (6H, m) and 2.01-1.59 (5H, m). Anal. Calcd for C23H27N4O7+H2O: C, 56.32; H, 6.16; N, 11.42. Found: C, 56.29; H, 6.11; N, 11.25. MS(FAB, m/z) 473 (M++1), 176, 149, 105, 91.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C([Li])CCC.[C:15](=[O:17])=[O:16]>C1COCC1.[OH-].[Na+]>[F:1][C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][C:7]=1[C:15]([OH:17])=[O:16]
Reactant: COc1ccccc1F
Reactant: O=C=O
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cccc(C(=O)O)c1F
Temperature: -78 °C

Procedure:
Pentamethylenediethylenetetramine (31.2 ml) was added to a solution of 2-fluoroanisole (15.0 g) in THF (450 ml). The reaction mixture was cooled to −78° C. and n-butyllithium (59.6 ml, 2.5M solution in hexanes) was added dropwise. Stirring was maintained for 2 h before the solution was added in a dropwise fashion to a flask containing solid carbon dioxide pellets. Upon complete addition (30 min) the mixture was allowed to warm to room temperature before removal of the volatiles in vacuo. The residue was dissolved in 10% sodium hydroxide solution (300 ml) and extracted with Et2O (3×). The aqueous was acidified to pH 1 with concentrated hydrochloric acid before extracting with DCM. The organics were washed with H2O, dried (MgSO4) and concentrated in vacuo to afford the subtitle compound as a yellow solid. Yield: 7.1 g.