Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[CH3:19][NH:20][CH3:21].C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:12]([CH3:13])[C:14]([N:20]([CH3:21])[CH3:19])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)OCc1ccccc1)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[(benzyloxy)carbonyl]-D-alanine (4.46 g), 11% dimethylamine methanol solution (11.0 mL) and N-ethyl-N-(1-methylethyl)propan-2-amine (5.17 g) in DMF (30 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (8.37 g) under ice-cooling. The reaction mixture was stirred at room temperature overnight, the reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.73 g).
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].C(=O)([O-])[O-].[Cs+].[Cs+].O.C([N:15]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)=[N:18][N:17]=[N:16]1)C=C>CN(C)C=O>[CH2:1]([N:16]1[N:17]=[N:18][C:19]([C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)=[N:15]1)[CH:2]=[CH2:3]
Reactant: C=CCn1nnnc1-c1ccc(-c2ccc(OCOC)cc2)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1nnc(-c2ccc(-c3ccc(OCOC)cc3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
Allyl bromide (0.27 ml, 3.13 mmol) and cesium carbonate (1.02 g, 3.13 mmol) were added to a solution of the obtained compound in N,N-dimethylformamide (5 ml), and the mixture was stirred at room temperature for 1 hour. After water was added to the reaction mixture and the mixture was extracted with ethyl acetate, the organic layer was washed with a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=2/1) to give a mixture of 1-allyl-5-(4′-methoxymethoxy-1,1′-biphenyl-4-yl)-1H-tetrazole and 2-allyl-5-(4′-methoxymethoxy-1,1′-biphenyl-4-yl)-2H-tetrazole (504 mg, two-step total yield: 71%).
Reaction SMILES: [CH:1]([NH:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([O:42][CH3:43])=[C:37]([CH:41]=1)[C:38](Cl)=[O:39].CS(C)=O>C1C=CC=CC=1>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([O:42][CH3:43])=[C:37]([CH:41]=1)[C:38]([N:14]([CH:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:39]
Reactant: CCOC(=O)CCCNC(c1ccccc1)c1ccccc1
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: c1ccccc1
Product: CCOC(=O)CCCN(C(=O)c1cc(Cl)ccc1OC)C(c1ccccc1)c1ccccc1
Yield: 99 %

Procedure:
Analogously to Example 19, 8.9 g of ethyl 4-benzhydrylaminobutyrate and 4.3 g of ethyl diisopropylamine are dissolved in 80 ml of benzene and reacted with a solution of 6.8 g of 5-chloro-2-methoxybenzoic acid chloride in 20 ml of benzene. As reaction product one obtains 13.8 g (99% of theory) of ethyl N-(5-chloro-2-methoxybenzoyl)-4-benzhydrylaminobutyrate as a viscous non-distillable oil. The saponification of this ester yields 11.1 g (85.6% of theory) of N-(5-chloro-2-methoxybenzoyl)-4-benzhydrylaminobutyric acid (M.P. 176° to 178°).
Reaction SMILES: O.O.[Sn](Cl)(Cl)(Cl)Cl.[F:8][CH:9]([F:24])[O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:12]=1[O:20][CH:21]([CH3:23])[CH3:22].[OH-].[Na+]>Cl.C(OCC)(=O)C>[F:8][CH:9]([F:24])[O:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=1[O:20][CH:21]([CH3:22])[CH3:23]
Reactant: CC(C)Oc1cc([N+](=O)[O-])ccc1OC(F)F
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)Oc1cc(N)ccc1OC(F)F
Reaction time: 1 h
Yield: 36.6 %

Procedure:
To tin chloride dihydrate (5.46 g, 24.2 mmol) in concentrated HCl (7 mL) at 0° C. was added 1-difluoromethoxy-2-isopropoxy-4-nitro-benzene (1.712 g, 6.92 mmol) in ethyl acetate (7 mL) and the reaction was stirred for 1 h. The reaction was adjusted to ˜pH7 with NaOH and was filtered through Celite, washing with ethyl acetate. The filtrate was separated and the aqueous phase was back extracted with ethyl acetate. The combined organic phase was washed with brine, dried (sodium sulfate) and evaporated. Purification by flash chromatography (SiO2) eluted with 2:8 ethyl acetate:hexanes provided 4-difluoromethoxy-3-isopropoxy-phenylamine (0.55 g, 37% yield, 57% yield based on recovered starting material) as an orange oil. 1H-NMR (CDCl3, 500 MHz) 6.94 (d, 1H), 6.41 (t, 1H), 6.31 (dd, 1H), 6.23 (d, 1H), 4.47 (m, 1H), 1.33 (d, 6H) ppm; MS (FIA) 218.2 (M+H); HPLC (Method A) 2.853 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.C([Li])CCC.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]2[N:23]=[C:22]([CH3:24])[O:21][C:20](=[O:25])[C:19]=2[CH:26]=1.Cl>O1CCCC1.C1C=CC=CC=1.CCCCCCC>[C:22]([NH:23][C:18]1[CH:17]=[CH:16][C:15]([Cl:14])=[CH:26][C:19]=1[C:20]([C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8])=[O:25])(=[O:21])[CH3:24]
Reactant: Cc1nc2ccc(Cl)cc2c(=O)o1
Reactant: Fc1cccc(F)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: c1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CC(=O)Nc1ccc(Cl)cc1C(=O)c1c(F)cccc1F
Reaction time: 0.83 h

Procedure:
To a solution of 114 g. (1.0 mole) of m-difluorobenzene in 800 ml. of dry tetrahydrofuran cooled to -50° C. and maintained under a nitrogen atmosphere was added, with stirring, 320 ml. of an n-heptane solution of n-butyl lithium containing 1.0 mole of the latter. The addition was carried out during 50 minutes and was followed by stirring 2 hours more at -50° C. The cold solution was then added with stirring during 50 minutes to a solution of 187.8 g. (0.97 mole) of 6-chloro-2-methyl-4H-3,1-benzoxazin-4-one [J. Am. Chem. Soc. 70, 2423 (1948)] in 1400 ml. of benzene and 1000 ml. of tetrahydrofuran at 25° C. The mixture was stirred under a nitrogen atmosphere for 20 hours, at which time 1000 ml. of 2N hydrochloric acid was added. The aqueous layer was separated and discarded. The organic layer was filtered to remove suspended solid material and the filtrate was washed with cold, dilute aqueous sodium hydroxide solution. Three layers were present, a light colored aqueous phase, a dark brown aqueous phase, and an organic phase. The organic phase, after being dried with anhydrous sodium sulfate, was concentrated to give 101 g. of a semi-solid which was then extracted with 2100 ml. of hot Skellysolve B hexanes. Evaporation of the extract gave 39.9 g. of crude product of melting point 106°-116° C. Recrystallization of this material from Skellysolve B gave purified 2-acetamido-5-chloro-2',6'-difluorobenzophenone of melting point 118°-120° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH2:18])=O)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:21].FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(OCC)(=O)C>O1CCOCC1.N1C=CC=CC=1>[Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[N:18])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:21]
Reactant: CN1Cc2c(C(N)=O)ncn2-c2ccc(F)c(Cl)c2C1=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CN1Cc2c(C#N)ncn2-c2ccc(F)c(Cl)c2C1=O
Reaction time: 3 h
Yield: 88.6 %

Procedure:
A suspension of 14.4 g (0.0466 mol) of 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-3-carboxamide in a mixture of 60 ml of dioxan and 8 ml of pyridine was treated dropwise at 0° with 6.8 ml (0.049 mol) of trifluoroacetic anhydride. The dark solution was stirred at 50° for 3 hrs., cooled, poured on to 400 ml of icewater, treated with ethyl acetate and extracted. The organic solution was filtered on 100 g of silica gel and rinsed with 200 ml of ethyl acetate. The product was recrystallized from m hot ethyl acetate. There were obtained 12 g (89%) of 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepine-3-carbonitrile as light yellowish crystals; m.p. 221°-223°.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:15])=[N:6][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1)([O-:3])=[O:2].[H-].[Na+].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][N:32]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].F[P-](F)(F)(F)(F)F.N1(O[P+](C(C)C)(C(C)C)C(C)C)C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[N+](C1C=CNN=1)([O-])=O.[H-].[Na+]>CN(C=O)C>[N+:1]([C:4]1[C:5]([NH:15][C:35]([C:34]2[CH:38]=[CH:39][C:31]([N:28]3[CH2:29][CH2:30][N:25]([C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[CH2:26][CH2:27]3)=[N:32][CH:33]=2)=[O:36])=[N:6][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1)([O-:3])=[O:2]
Reactant: Nc1nn(-c2ccccc2)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cn2)CC1
Agent: CC(C)[P+](On1nnc2ccccc21)(C(C)C)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)Nc3nn(-c4ccccc4)cc3[N+](=O)[O-])cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-nitro-1-phenyl-1H-pyrazol-3-amine (0.05 g, 0.25 mmol) in DMF (0.75 mL) was treated with sodium hydride (6 mg (60% in mineral oil), 0.27 mmol). In a separate flask 6-[4-(tert-butoxycarbonyl)piperazin-1-yl]nicotinic acid (0.075 g, 0.25 mmol) in DMF (0.75 mL) was treated with (1H-1,2,3-benzotriazol-1-yloxy)(triisopropyl)phosphonium hexafluorophosphate (0.16 g, 0.37 mmol) and this was stirred at ambient temperature for 1 hour. The acid/BOP solution was then transferred to the nitropyrazole/sodium hydride solution and the resulting reaction mixture was stirred at ambient temperature for 16 hours. The reaction was loaded directly onto a silica cartridge and purified by flash chromatography (20-30% ethyl acetate/hexanes) to give tert-butyl 4-(5-{[(4-nitro-1-phenyl-1H-pyrazol-3-yl)amino]carbonyl}pyridin-2-yl)piperazine-1-carboxylate as a yellow oil. ESIMS calcd 494.2 (M++H), found 494.1 (M++H).
Reaction SMILES: Br[C:2]([C:5](=[O:7])[CH3:6])=[CH:3]O.[NH2:8][C:9]([NH2:11])=[O:10]>CC(C)=O>[C:5]([C:2]1[O:10][C:9]([NH2:11])=[N:8][CH:3]=1)(=[O:7])[CH3:6]
Reactant: NC(N)=O
Reactant: CC(=O)C(Br)=CO
Solvent: CC(C)=O
Product: CC(=O)c1cnc(N)o1
Reaction time: 1 h
Yield: 49.9 %

Procedure:
A mixture of 132.3 g (0.80 mole) of 2-bromo-1-hydroxy-3-oxo-1-butene, 120.1 g (2.0 mole) of urea, and 1.85 1 of acetone was heated at reflux with overhead stirring for one hour. The mixture was concentrated and the oil residue was taken up into 600 ml of water, then made basic with concentrated ammonium hydroxide. After sitting at room temperature for 0.5 hour, a precipitate formed. This was collected, and dried in vacuo to give 61.1 g of crude product. The filtrate was again concentrated and the oil residue taken up in 50 ml of water and again made basic with concentrated ammonium hydroxide. After sitting overnight a second crop of crude product, amounting to 17.6 g was isolated. Both crops were combined and recrystallized from methanol to give 50.3 g (50%) of 5-acetyl-2-aminooxazole, m.p. 214°-215° C.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][CH2:5][CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:16]([O-])=O)[CH:13]=2)[N:8]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:7]1=[O:28].O.NN.N>CO.[Ni].CO.C(Cl)Cl>[NH2:16][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:7](=[O:28])[CH:6]([CH2:5][CH2:4][CH2:3][N:2]([CH3:29])[CH3:1])[CH2:15]2
Reactant: COc1ccc(CN2C(=O)C(CCCN(C)C)Cc3cc([N+](=O)[O-])ccc32)cc1
Agent: [Ni]
Agent: N
Agent: NN
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COc1ccc(CN2C(=O)C(CCCN(C)C)Cc3cc(N)ccc32)cc1
Yield: 72.3 %

Procedure:
A solution of 3-(3-(dimethylamino)propyl)-1-(4-methoxybenzyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (115 mg, 0.29 mmol) in 10 mL methanol was added to Raney Nickel (slurry in H2O, 50 mg) in a round bottom flask. The suspension was treated with hydrazine hydrate (90 μL, 2.90 mmol) and heated at reflux for 10 minutes then filtered through a pad of celite. The celite pad was rinsed with 10 mL methanol. The filtrate was concentrated to give a yellow residue which was subjected to flash silica gel chromatography using 5% 2M NH3 in MeOH/CH2Cl2 to give a yellow semi-solid (77 mg, 72.3%). 1H-NMR (CDCl3) δ: 7.13-7.10 (m, 2H), 6.83-6.80 (m, 2H), 6.69 (d, J=8.4 Hz, 1H), 6.50 (d, J=2.4 Hz, 1H), 6.42 (dd, J=2.4, 8.4 Hz, 1H), 5.05 (dd, J=15.6, 29.1 Hz, 2H), 3.76 (s, 3H), 3.48 (br s, 2H), 3.01-2.91 (m, 1H), 2.70-2.58 (m, 2H), 2.28 (t, J=7.2 Hz, 2H), 2.21 (s, 6H), 1.88-1.42 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH:29]([CH3:31])[CH3:30])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23]O)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.S(Cl)(Cl)=O.[Cl-].[CH:37]([NH:40][CH3:41])([CH3:39])[CH3:38]>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:27]([CH:29]([CH3:31])[CH3:30])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23][N:40]([CH:37]([CH3:39])[CH3:38])[CH3:41])=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: CNC(C)C
Reactant: CC(C)N(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)N(C)Cc1cnnn1-c1cccc(C2=Nc3cc(N(C)C(C)C)c(Cl)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isopropyl-methyl-amino)-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 96) (220 mg, 0.50 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with N-isopropylmethylamine in DMF according to the method described in Example 45. Obtained as a light yellow solid (120 mg, 49%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[Li+].CC([N-]C(C)C)C.[CH2:21]1[CH:23]([CH:24]([OH:27])C#N)[CH2:22]1>C1COCC1.S([O-])(O)(=O)=O.[K+]>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:24]([CH:23]2[CH2:21][CH2:22]2)[OH:27])[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)Cc1ccc(F)c(F)c1
Reactant: N#CC(O)C1CC1
Agent: CC(C)[N-]C(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)C(c1ccc(F)c(F)c1)C(O)C1CC1
Temperature: 25 °C
Yield: 34.4 %

Procedure:
A solution of 3,4-difluorophenylacetic acid (2.9 g, 16.8 mmol) in 80 mL dry THF was cooled to −78° C. and treated with LDA (2.0 M heptane/THF/ethylbenzene, 42 mmol, 21 mL) for 15 minutes. Then cyclopropylcarboxaldehyde (17 mmol, 1.27 mL, 1.19 g) was added via syringe and the reaction warmed slowly to room temperature over 1 hr. The reaction mixture was diluted with 5% aqueous potassium hydrogen sulfate (50 mL), and extracted with ethyl acetate (2×150 mL). The combined extracts were dried (Na2SO4), filtered and concentrated in vacuo. The lower rf material crystallized to give 1.4 g of solid. 1H NMR (CDCl3, 300 MHz) δ 7.40-7.00 (m, 3H, Ar—H), 3.75-3.60 (br m, 1H), 3.50-3.40 (m, 1H), 0.95-0.70 (m, 1H), 0.5-0.20 (m, 4H).
Reaction SMILES: [N+:1]([CH:3](S(C1C=CC(C)=CC=1)(=O)=O)[CH3:4])#[C-:2].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][C:17]=1[F:24].C([O-])([O-])=O.[K+].[K+].O>CO>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]2[O:21][CH:2]=[N:1][C:3]=2[CH3:4])=[CH:18][C:17]=1[F:24]
Reactant: O=Cc1ccc(Cl)c(F)c1
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ncoc1-c1ccc(Cl)c(F)c1
Yield: 85.7 %

Procedure:
A mixture of 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (1.56 g, 7.44 mmol), 4-chloro-3-fluorobenzaldehyde (1.18 g, 7.44 mmol), and K2CO3 (2.06 g, 14.9 mmol) in MeOH (35 mL) was heated to reflux. After 1.5 hr water (200 mL) was added and the product was extracted with EtOAc (200 mL). The organic layer was washed with brine and dried over Na2SO4, filtered, and concentrated to an orange oil. Chromatography on silica gel (Analogix® SF25-40G, 0%-30% EtOAc/hexanes, 30 mL/min) afforded 1.35 g (86%) of the title compound as a yellow solid. 1H NMR (300 MHz, CH3OH-d4) δ 8.18 (s, 1H), 7.62-7.55 (m, 1H), 7.52 (dd, J=1.9, 10.3, 1H), 7.49-7.44 (m, 1H), 2.42 (s, 3H). MS (DCI+) m/z 212 (M+H).
Reaction SMILES: [C:1]1([N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[CH2:23]1COCC1>>[C:1]1([N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[CH2:23])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCOC1
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: C=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reaction time: 2 h
Yield: 89 %

Procedure:
Thereafter, 20 g (0.066 mol) of 4-(diphenylamino)benzaldehyde (1) dissolved in 40 ml of THF was charged into the dropping funnel, and was gradually added dropwise to the mixture. After the addition, a reaction was caused at room temperature for 2 hours. Then, 70 ml of water was added thereto. The product was extracted with ethyl acetate, and the extract was washed with water until neutralized. The organic phase was dried, concentrated and then purified by column chromatography. Pale yellow crystals of 4-(diphenylamino)styrene (3) (16 g, yield: 89%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.Br[C:18]1[CH:19]=[CH:20][C:21]2[N:25]=[C:24]([C:26](=[O:28])[CH3:27])[N:23]([CH3:29])[C:22]=2[CH:30]=1.CNCCNC.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu](I)I>[C:26]([C:24]1[N:23]([CH3:29])[C:22]2[CH:30]=[C:18]([N:11]3[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]4[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=4)=[CH:9][C:10]3=[O:14])[CH:19]=[CH:20][C:21]=2[N:25]=1)(=[O:28])[CH3:27]
Reactant: O=c1cc(OCc2ccc(Cl)cc2)cc[nH]1
Reactant: CC(=O)c1nc2ccc(Br)cc2n1C
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CC(=O)c1nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc2n1C
Temperature: 150 °C
Reaction time: 1 h
Yield: 1.6 %

Procedure:
A mixture of 4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (596 mg), 1-(6-bromo-1-methyl-1H-benzimidazol-2-yl)ethanone (640 mg), N,N′-dimethylethylenediamine (0.272 ml), copper iodide (482 mg) and potassium carbonate (699 mg) in DMSO (10 ml) was stirred at 150° C. for 1 h. The mixture was quenched with NH3 solution and extracted with EtOAc twice. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from EtOH to give the title compound (16.8 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C=O)C>[Si:17]([O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH2:1])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cc([N+](=O)[O-])ccc1N
Temperature: 23 °C
Reaction time: 48 h
Yield: 97.6 %

Procedure:
To a solution of 2-amino-5-nitrophenol (1 g, 6.49 mmol) and imidazole (0.88 g, 12.3 mmol) in DMF (15 mL), tert-butyldimethylsilyl chloride (11.2 mL, 64.9 mmol) was added. The resulting mixture was allowed to stir at 23° C. for 48 hours. The reaction mixture was partitioned between 0.1% HCl and ethyl acetate. The combined organic phase was washed with brine, dried over MgSO4 and filtered. Removal of solvent at reduced pressure and chromatography of the resulting oil on silica gel (hexane:ethyl acetate; 5:1) gave the tided compound (1.7 g, 98%). 1H NMR (CDCl3): δ 7.78 (dd, 1H, J=6.7 Hz and J=2.7 Hz), 7.61 (d, 1H, J=2.7 Hz), 6.7 (d, 1H, J=8.8 Hz), 1.0 (s, 9H), 0.28 (s, 6H).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].O>C1COCC1>[CH3:19][S:20]([N:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1)(=[O:22])=[O:21]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1CCN(S(C)(=O)=O)CC1
Reaction time: 1 h
Yield: 92 %

Procedure:
Ethyl isonipecotate (31.44 g, 200 mmol) and triethylamine (50.2 ml, 360 mmol) were dissolved in THF (500 ml), and under ice cooling, to the solution was added dropwise methanesulfonyl chloride (23.2 ml, 300 mmol). The mixture was stirred at the same temperature for 1 hour. Under ice cooling, water (200 ml) was added, and the organic layer was distilled off under reduced pressure. The aqueous layer was extracted with ethyl acetate (200 ml, 100 ml×2). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (50 ml×2), 1N-hydrochloric acid (50 ml×3), saturated sodium chloride solution (50 ml), successively, dried over magnesium sulfate and concentrated under reduced pressure. To the concentrate was added diisopropyl ether (100 ml), and the resulting precipitates were collected by filtration. The precipitates were washed with diisopropyl ether (50 ml×3), and dried under reduced pressure to give the titled compound (43.20 g, 184 mmol, Yield 92%) as white crystals.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[N:12]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:11]=1.CI.O>C1COCC1.ClCCl>[CH3:1][C:11]1[N:12]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:20])=[O:21])[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:18]2[C:10]=1[CH3:9]
Reactant: Cc1cn(S(=O)(=O)c2ccccc2)c2ncccc12
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(C)n(S(=O)(=O)c2ccccc2)c2ncccc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
Lithium diisopropylamide (0.88 mL, 1.52 mmol, 1.8M in heptane/THF/ethylbenzene) was added to a solution of 3-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.20 g, 0.734 mmol) in THF (4.0 mL) at −78° C. The slurry was stirred at −78° C. for 30 minutes, and then methyl iodide (0.059 mL, 0.952 mmol) was added. The reaction mixture was allowed to warm up to room temperature and stirred for 2 hours. Water was then added to the mixture followed by dichloromethane. The layers were separated. The aqueous layer was extracted twice with dichloromethane. The organic layers were dried with sodium sulfate, filtered and concentrated in vacuo. The crude was purified by flash chromatography to afford 2,3-dimethyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.17 g, 99%) as a solid (purity 80%).