Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.CC([Mg]Cl)C.[CH2:15]([N:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[CH2:15]([N:22]1[CH2:27][CH2:26][C:25]([OH:28])([C:2]2[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:24][CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: OCc1cccnc1Br
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OCc1cccnc1C1(O)CCN(Cc2ccccc2)CC1
Yield: 17.6 %

Procedure:
To a solution of 4.0 g (21 mmol) (2-bromo-pyridin-3-yl)-methanol in 105 ml dry tetrahydrofuran were added 22 ml (45 mmol) 2-propylmagnesium chloride solution (2.0 M in tetrahydrofuran). The reaction mixture was heated at reflux for 2 h. A solution of 3.8 g (21 mmol) 1-benzyl-4-piperidone in 22 ml tetrahydrofuran was added dropwise at a temperature of approximately 65° C. The reaction mixture was heated at reflux for 3 h and then quenched with water. The aqueous layer was basified to pH 9 with aqueous 1 M sodium hydroxide and extracted with three portions of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. Flash-chromatography gave the title compound (1.1 g, 17%) as a brown solid.
Reaction SMILES: CS(C)=O.[NH:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13](Br)[CH:12]=1.[OH-].[K+]>C(OC(=O)C)C>[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([N:5]2[CH:9]=[CH:8][N:7]=[CH:6]2)[CH:12]=1
Reactant: COc1ccc(C)cc1Br
Reactant: c1c[nH]cn1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(C)cc1-n1ccnc1
Temperature: 140 °C
Reaction time: 24 h
Yield: 57 %

Procedure:
To a degassed DMSO (20 mL) solution of imidazole (1.0 g, 15 mmol) was added 4-methyl-2-bromoanisole (1.25 mL, 10 mmol), KOH (1.12 g, 20 mmol) and Cu2O (280 mg, 2 mmol) under nitrogen. The resulting mixture was stirred at 140° C. for 24 hrs under N2. After cooling to room temperature, the mixture was poured into ethylacetate (EA) (50 mL) and filtered. The filtrate was washed with water (50 mL×3) and dried over anhydrous magnesium sulfate. After rotary evaporation, the crude oil was purified via column chromatography on silica gel with eluent of EA/MeOH (9/1, v/v), affording a light yellow solid (57%). 1H-NMR (300 MHz, CDCl3) δ(ppm) 7.78 (s, 1H), 7.16 (m, 3H), 7.09 (d, J=1.8 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 3.81 (s, 3H), 2.33 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[N:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH2:14]([N:16]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[C:17](=[O:27])[CH2:18][NH:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)[CH3:15]>>[CH3:1][N:2]([CH3:13])[C:3]1[N:8]=[CH:7][C:6]([S:9]([N:19]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[CH2:18][C:17]([N:16]([CH2:14][CH3:15])[CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[O:27])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CCN(Cc1ccccn1)C(=O)CNc1ccc(C)cc1
Reactant: CN(C)c1ccc(S(=O)(=O)Cl)cn1
Product: CCN(Cc1ccccn1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(N(C)C)nc1

Procedure:
prepared by reaction of 6-dimethylamino-pyridine-3-sulfonyl chloride with N-ethyl-N-pyridin-2-ylmethyl-2-p-tolylamino-acetamide
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:14]([CH3:15])[CH2:13][N:12]([C:16]2[C:21]([N+:22]([O-])=O)=[CH:20][N:19]=[CH:18][C:17]=2[CH3:25])[CH2:11][C@H:10]1[NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl-].[NH4+]>CCO.O.[Fe]>[NH2:22][C:21]1[CH:20]=[N:19][CH:18]=[C:17]([CH3:25])[C:16]=1[N:12]1[CH2:13][C@H:14]([CH3:15])[C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])[C@H:10]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:11]1
Reactant: Cc1cncc([N+](=O)[O-])c1N1C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1cncc(N)c1N1C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.6 %

Procedure:
A mixture of tert-butyl [(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methyl-1-(3-methyl-5-nitropyridin-4-yl)piperidin-3-yl]carbamate (12 mg, 0.025 mmol), iron powder (38 mg, 0.68 mmol) and ammonium chloride (55 mg, 1.0 mmol) in EtOH (0.9 mL) and water (0.2 mL) was stirred at room temperature for 16 h. A second aliquot of iron powder (380 mg), ammonium chloride (550 mg), and EtOH (1 mL) were added and stirring was continued at 55° C. for 3 h. The crude reaction mixture was filtered through a pad of diatomaceous earth and the inorganics were washed thoroughly with EtOAc. The filtrate was concentrated under reduced pressure to give the sub-title compound (11 mg, 100%), which was used directly in the subsequent reaction without further purification. LCMS (ESI) calc. for C23H43N4O3Si [M+H]+: m/z=451.3. found 451.2.
Reaction SMILES: C([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21](=[O:30])[CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[O:19])=[C:13]([Cl:31])[CH:12]=2)[CH:7]=[CH:6][N:5]=1)(=O)N.C[N:33](C=O)C>>[NH2:33][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21](=[O:30])[CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[O:19])=[C:13]([Cl:31])[CH:12]=2)[CH:7]=[CH:6][N:5]=1
Reactant: NC(=O)c1cc(Oc2ccc(NC(=O)NC(=O)Cc3ccc(F)cc3)c(Cl)c2)ccn1
Reactant: CN(C)C=O
Product: Nc1cc(Oc2ccc(NC(=O)NC(=O)Cc3ccc(F)cc3)c(Cl)c2)ccn1
Yield: 55 %

Procedure:
Prepared in a manner similar to that which is described for Example 91. 1-(4-(2-Carbamoylpyridin-4-yloxy)-2-chlorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea (18 mg, 0.04 mmol) in DMF (1.0 mL) was converted to 1-(4-(2-aminopyridin-4-yloxy)-2-chlorophenyl)-3-(2-(4-fluorophenyl)acetyl)urea (10 mg, 55% yield). 1H NMR (DMSO-d6) δ 13.47 (s, 1H), 11.26 (s, 1H), 11.08 (s, 1H), 8.37 (d, 1H, J=8.5 Hz), 7.95 (d, 1H, J=7.5 Hz), 7.88 (s, 2H), 7.62 (s, 1H), 7.35 (m, 3H), 7.17 (m, 2H), 6.64 (d, 1H, J=7.5 Hz), 6.13 (s, 1H), 3.76 (s, 2H); MS (ESI+): m/z 415.18/417.17 (M+H)+.
Reaction SMILES: OC[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:6]#[N:7].[C:15]([Br:19])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:19][C:15]1[C:4]([CH3:3])=[C:5]([CH:8]=[C:9]([C:11]([F:12])([F:14])[F:13])[CH:10]=1)[C:6]#[N:7]
Reactant: BrC(Br)(Br)Br
Reactant: N#Cc1cc(CO)cc(C(F)(F)F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1c(Br)cc(C(F)(F)F)cc1C#N
Reaction time: 0.5 h
Yield: 83 %

Procedure:
3-Hydroxymethyl-5-trifluoromethyl-benzonitrile (23.4 g) is dissolved in methylene chloride (230 mL) and thereto is added carbon tetrabromide (42.4 g), followed by an addition of triphenylphosphine (32.0 g) under ice-cooling and the mixture is stirred at the same temperature for 30 minutes. The reaction solution is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give 3-bromo-methyl-5-trifluoromethyl-benzonitrile (25.5 g). NMR (CDCl3): 4.51 (2H, s), 7.86 (1H, s), 7.88 (2H, s)
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)([O-:3])=[O:2].[H-].[Na+].[S:15](Cl)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16]>CN(C=O)C>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:15]([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16])([O-:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c([N+](=O)[O-])cccc32)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 4-nitro-1H-indole (CAS #: 4769-97-5) (10.4 g, 64.1 mmol) in DMF (401 mL) at 0° C. was added NaH (60% in mineral oil, 3.85 g, 96 mmol), and the mixture was stirred at 0° C. After 15 minutes, to the red suspension was added TsCl (14.67 g, 77 mmol). The reaction turned yellow and was warmed to room temperature. After 15 minutes the reaction was quenched by ice/H2O, and the mixture was stirred for 30 minutes at room temperature. The precipitate was collected by filtration to provide the title compound, which was used in the next reaction without any further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.43 (d, J=8.34 Hz, 1H) 8.15-8.29 (m, 2H) 7.96 (m, 2H) 7.60 (t, J=8.21 Hz, 1H) 7.42 (m, J=7.83 Hz, 2H) 7.26-7.38 (m, 1H) 2.33 (s, 3H)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([S:26](=[O:33])(=[O:32])[N:27]([CH3:31])[CH2:28][CH2:29][CH3:30])=[CH:14][C:10]=1[C:11](Cl)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:34][C:35]1[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=1[NH2:37]>>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:15]([S:26](=[O:32])(=[O:33])[N:27]([CH3:31])[CH2:28][CH2:29][CH3:30])=[CH:14][C:10]=1[C:11]([NH:37][C:36]1[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=1[Cl:34])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCN(C)S(=O)(=O)c1cc(C(=O)Cl)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: Nc1ccccc1Cl
Product: CCCN(C)S(=O)(=O)c1cc(C(=O)Nc2ccccc2Cl)c(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
2.10 Reaction of 2,4-dibenzyloxy-5-(N-methyl-N-propylsulfamoyl)benzoyl chloride with 2-chloroaniline gives the compound 2,4-dibenzyloxy-5-(N-methyl-N-propylsulfamoyl)-N-(2-chlorophenyl)benzamide.
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=3[O:20][CH2:21]OC)[O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.COC1C=CC(OC)=CC=1C1OC2C=CC=C(C)C=2N=1>>[Br:1][CH2:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=3[O:20][CH3:21])[O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COCOc1ccc(OC)cc1-c1nc2c(CBr)cccc2o1
Agent: COc1ccc(OC)c(-c2nc3c(C)cccc3o2)c1
Product: COc1ccc(OC)c(-c2nc3c(CBr)cccc3o2)c1

Procedure:
4-bromomethyl-2-(2,5-dimethoxyphenyl)benzoxazole (F14) was prepared in a similar manner for the preparation of 4-bromomethyl-2-(5-methoxy-2-methoxymethoxyphenyl)benzoxazole (F12) by using 2-(2,5-dimethoxyphenyl)-4-methylbenzoxazole (F10) (4.55 g, 16.9 mmol) instead of 2-(5-methoxy-2-methoxymethoxyphenyl)-4-methylbenzoxazole (F8) in 56% (3.30 g): 1H-NMR (500 MHz, CDCl3) δ3.60 (s, 3H), 3.97 (s, 3H), 3.99 (s, 3H), 4.96 (s, 2H), 5.31 (s, 2H), 6.85 (s, 1H), 7.30 (t, 1H, J=8.0 Hz), 7.40 (d, 1H, J=8.0 Hz), 7.51 (d, 1H, J=8.0 Hz), 7.66 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:14])[N:5]([CH3:13])[C:6](=[O:12])[NH:7]2.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C(N(CC)CC)C>[CH3:13][N:5]1[C:4](=[O:14])[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[NH:7][C:6]1=[O:12]
Reactant: C#C[Si](C)(C)C
Reactant: Cn1c(=O)[nH]c2cccc(Br)c2c1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c2cccc(C#C[Si](C)(C)C)c2c1=O
Temperature: 70 °C
Reaction time: 4 h
Yield: 46 %

Procedure:
To a degassed solution of 5-bromo-3-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline (1.Og,4.Ommol) in 20 ml of DMF and 20 ml of triethylamine was added trimethylsilylacetylene (1.6ml,12mmol), 50mg of triphenylphosphine, 20mg of palladium(Il)acetate, and 1 mg of cuprous(I)iodide. The mixture was stirred under nitrogen, at 70° C.. After 7h additionally 0.4ml of trimethylsilylacetylene was added and hating continued for 4h. Then the mixture was evaporated in vacuo and the residue extracted with 100 ml of dichloromethane and 100 ml of water. The organic layer was washed twice with 100 ml of water dried over anhydrous sodium sulfate, treated with charcoal, filtered through a pad of celite, and evaporated. The residue was triturated with ether/petroleum ether (1:1) and filtered off and dried giving 0.50g (46%) of 1,2,3,4-tetrahydro-3-methyl-2,4-dioxo5-trimethylsilylethynyl-quinazoline.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)=[CH2:2].CC(O)=O.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCO>[CH2:13]([NH:20][CH2:2][CH2:1][C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: C=Cc1ncccn1
Solvent: CCO
Solvent: CC(=O)O
Product: c1ccc(CNCCc2ncccn2)cc1

Procedure:
To a solution of 2-vinylpyrimidine (1.55 g, 14.6 mmol) in EtOH (15 mL) at room temperature was added AcOH (2.0 mL) and benzylamine (3.14 g, 29.3 mmol) (3.2 mL). The reaction mixture was heated to reflux for 18 h, and concentrated. Diluted with EtOAc, washed with 5 M NaOH (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 2% to 10% MeOH in DCM) gave N-benzyl-2-(pyrimidin-2-yl)ethanamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[CH2:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH3:12]>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([N:16]2[CH2:17][CH2:18][N:13]([CH2:11][CH3:12])[CH2:14][CH2:15]2)=[O:9])[CH:3]=1
Reactant: O=C(Cl)c1cc(Cl)ccn1
Reactant: CCN1CCNCC1
Product: CCN1CCN(C(=O)c2cc(Cl)ccn2)CC1

Procedure:
Using 4-chloropicolinic acid chloride and N-ethylpiperazine instead of N-Boc-piperazine, amidation was carried out in the same manner as Step A in Example 1-D-199, to obtain (4-chloro-pyridin-2-yl)-(4-ethyl-piperazin-1-yl)-methanone. Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (232 mg, 0.430 mmol), and the obtained (4-chloro-pyridin-2-yl)-(4-ethyl-piperazin-1-yl)-methanone (120 mg, 0.473 mmol) instead of 4-chloropicolinic acid t-butylamide, amination was carried out in the same manner as Example 1-D-07, to obtain a crude product of [4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-pyridin-2-yl]-(4-ethyl-piperazin-1-yl)-methanone as a yellow solid (225 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-201) as a yellow powder (85 mg, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=O)[C:18]3[C:13]4=[C:14]([O:28][CH2:29][CH2:30][N:12]4[CH:11]=2)[CH:15]=[C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:52])=CC=1.C1(C)C=CC=CC=1>ClC(Cl)C.C(Cl)Cl>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[S:52])[C:18]3[C:13]4=[C:14]([O:28][CH2:29][CH2:30][N:12]4[CH:11]=2)[CH:15]=[C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cn2c3c(cc(CN4CCOCC4)cc3c1=O)OCC2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc(Cl)cc1)c1cn2c3c(cc(CN4CCOCC4)cc3c1=S)OCC2
Temperature: 25 °C
Yield: 3.9 %

Procedure:
A mixture of N-(4-Chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide (1.20 g, 2.64 mmol) of preparation 6 is dissolved in dichloroethane (160 mL) followed by the addition of KHMDS (0.5 M, 5.3 mL, 2.64 mmol, 1 equiv.). Then Lawesson's reagent (2.1 g, 5.28 mmol, 2.0 equiv) and toluene (160 mL) is added and the resulting mixture is heated at reflux for 24 h. The reaction is cooled to room temperature, diluted with DCM, washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography (heptane/EtOAc 4/1, 1/1, 1/4, 0/1 then DCM/MeOH 19/1) and then repurified by silica gel chromatography (DCM/MeOH 11/0, 45/1, 9/1) to afford 48 mg of the title compound as a solid.
Reaction SMILES: [CH2:1]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22]C3C=C(F)C(C#N)=C(F)C=3)=O)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(OCC1C=CC(C2C=CC(C(O)=O)=CC=2)=CC=1)CCCC.S(Cl)([Cl:57])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([Cl:57])=[O:22])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOCc1ccc(-c2ccc(C(=O)Oc3cc(F)c(C#N)c(F)c3)cc2)cc1
Reactant: O=S(Cl)Cl
Agent: CCCCCOCc1ccc(-c2ccc(C(=O)O)cc2)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCOCc1ccc(-c2ccc(C(=O)Cl)cc2)cc1

Procedure:
Preparation of 3,5-difluoro-4-cyanophenyl 4'-(pentyloxymethyl)biphenyl-4-carboxylate (in the formula (1), R=C5 H11, l=1, m and n=both, 1, o=0, A1 and A2 =both, 1,4-phenylene group, Z1 =covalent bond, Z2 =--COO--, X=CN, and Y1 and Y2 =both, F) (Compound No. 229) 4'-(Pentyloxymethyl)biphenyl-4-carboxyic acid (2.1 g, 7.0 mmol) was mixed with thionyl chloride (1.3 g, 10.6 mmol), pyridine (0.1 ml) and toluene (4 ml), followed by reacting them at 80° C. for 2 hours, and distilling off superfluous thionyl chloride and toluene under reduced pressure, to obtain raw 4'-(pentyloxymethyl)biphenyl-4-carbonyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7](Cl)=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1.[F:18][C:19]1[C:24](C2C([N+]([O-])=O)=CC(C#N)=CC=2[N+]([O-])=O)=[CH:23][C:22]([CH3:39])=[CH:21][N:20]=1>>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([C:24]2[C:19]([F:18])=[N:20][CH:21]=[C:22]([CH3:39])[CH:23]=2)=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1
Reactant: Cc1cnc(F)c(-c2c([N+](=O)[O-])cc(C#N)cc2[N+](=O)[O-])c1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Product: COC(=O)c1cc([N+](=O)[O-])c(-c2cc(C)cnc2F)c([N+](=O)[O-])c1
Yield: 94 %

Procedure:
The title compound was prepared from 4-chloro-3,5-dinitro-benzoic acid methyl ester in 94% yield according to the procedure outline for the preparation of Compound 122. MS (ES) [m+H] calc'd for C14H10FN3O6, 336; found 336.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([NH:7][N:8]=[CH:9][C:10](Cl)=[O:11])=[CH:3][CH:2]=1.[OH-].[Na+].[CH3:16]O>>[C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([N:7]2[CH:16]=[C:10]([OH:11])[CH:9]=[N:8]2)=[CH:3][CH:2]=1
Reactant: CO
Reactant: Cc1ccc(NN=CC(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(-n2cc(O)cn2)cc1
Reaction time: 2.5 h

Procedure:
(p-Tolyl-hydrazono)-acetyl chloride (4.0 g, 19.04 mmol) was then taken in methanol and sodium hydroxide (1.52 g, 38.0 mmol) was added. And the reaction mixture was stirred for 2.5 hours. Methanol was removed and residue was taken up in water and pH was made 3 by adding dilute HCl. The solid was filtered off through on Buckner funnel, washed with cold water, dried under vacuum, and further washed with petroleum ether and dried under vacuum.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][C:9]([OH:11])=O)[CH:2]=1.C1C[N:24]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)[CH2:23]C1.F[P-](F)(F)(F)(F)F.CN>C(Cl)Cl>[CH3:23][NH:24][C:9](=[O:11])[CH2:8][CH:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:12]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1
Reactant: O=C(O)CC(c1cccnc1)c1c[nH]c2ncccc12
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CNC(=O)CC(c1cccnc1)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
To a RT suspension of 3-pyridin-3-yl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propionic acid (810 mg, 3.03 mmol) in DCM (30 mL) was added TEA (0.63 mL, 4.54 mmol) followed by PyBOP (1.73 g, 3.33 mmol) and MeNH2 (2 M in THF, 2.27 mL, 4.54 mmol). After stirring the reaction mixture at RT for 30 min, the beige precipitate was filtered off, and the filtrate was concentrated. The crude residue was purified via flash chromatography (DCM/MeOH/NH4OH) to afford N-Methyl-3-pyridin-3-yl-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-propionamide as a yellow oil (525 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].Cl[CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][CH3:30])[CH2:19][CH2:18]1.Cl>>[CH2:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:20]1[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][CH2:14][O:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][CH2:6][C:7]3=[O:12])[CH2:18][CH2:19]1)[CH3:30]
Reactant: CCc1ccccc1N1CCN(CCCCl)CC1
Reactant: O=C1CCCc2c(O)cccc21
Agent: Cl
Product: CCc1ccccc1N1CCN(CCCOc2cccc3c2CCCC3=O)CC1
Yield: 70 %

Procedure:
from 5-hydroxy-1-oxotetraline and 1-(3-chloropropyl)-4-(2-ethylphenyl)-piperazine; yield 70% of theory; m.p. of the hydrochloride (recrystallized from water) 209°-210°C;
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:12]=2[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1.CN(C1C=CC=CN=1)C.Cl>C(Cl)Cl.C(Cl)CCl>[C:1]1([S:7]([NH:10][C:11]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:12]=2[C:13]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=2)=[O:15])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=C(O)c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.8 %

Procedure:
To a suspension of 2-phenylsulfonylamino-5-chlorobenzoic acid (250 mg; prepared in Reference Example 3.) and methyl p-aminobenzoate (133 mg) in methylene chloride (5 ml), EDC (168 mg) and dimethylaminopyridine (20 mg) were added. The mixture was stirred for 3 days at room temperature. The reaction mixture was poured into diluted HCl and extracted with ethyl acetate. The organic layer was washed, dried over and concentrated under reduced pressure. The residue was purified on silica gel column chromatography (AcOEt-benzene) to give the title compound (142 mg) having the following physical data.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]1[NH:15][C:14]([CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[N:13][C:12]=1[CH3:22].CC1C=C(C)C(C2N=C(C3CCOCC3)NC=2C)=CC=1C(O)=O.Cl.[F:47][C:48]1([C:52]2[CH:59]=[CH:58][C:55]([C:56]#[N:57])=[CH:54][CH:53]=2)[CH2:51][NH:50][CH2:49]1.Cl.N1CC(C2C=CC(C#N)=CC=2)C1>>[F:47][C:48]1([C:52]2[CH:53]=[CH:54][C:55]([C:56]#[N:57])=[CH:58][CH:59]=2)[CH2:49][N:50]([C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([C:11]3[NH:15][C:14]([CH:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)=[N:13][C:12]=3[CH3:22])[CH:4]=2)[CH2:51]1
Reactant: N#Cc1ccc(C2(F)CNC2)cc1
Reactant: Cc1ccc(C(=O)O)cc1-c1[nH]c(C2CCOCC2)nc1C
Agent: Cc1cc(C)c(-c2nc(C3CCOCC3)[nH]c2C)cc1C(=O)O
Agent: Cl
Agent: N#Cc1ccc(C2CNC2)cc1
Product: Cc1ccc(C(=O)N2CC(F)(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(C2CCOCC2)nc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 164, except 4-methyl-3-(4-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)benzoic acid (compound 168.1) was used in place of 2,4-dimethyl-5-(4-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)benzoic acid (compound 164.2) and 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4) was used in place of 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2). m/z (ES+) 459 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:18]>C(Cl)Cl>[C:9]([N+:8]([O-:18])=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)NCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)[N+]([O-])=Cc1ccccc1

Procedure:
Following the general procedure of Example 1, N-benzyl-N-tert-butylamine is oxidized using a solution of 3-chloroperoxybenzoic acid dissolved in methylene chloride to give N-tert-butyl-alpha-phenyl nitrone as a white solid melting at 70°-72° C. This is the nitrone described in Japanese Sho No. 59-11345.