Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][NH:5][C:4]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[H-].[Na+].[C:20]([O:24][C:25]([N:27]1[CH2:31][CH2:30]OS1(=O)=O)=[O:26])([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C>[C:20]([O:24][C:25]([NH:27][CH2:31][CH2:30][N:5]1[CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:2][CH3:1])=[C:4]1[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCOS1(=O)=O
Reactant: CCOC(=O)c1c[nH]c(C(=O)OCC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CCNC(=O)OC(C)(C)C)c(C(=O)OCC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of diethyl 3-methoxy-1H-pyrrole-2,4-dicarboxylate (93 mmol) in DMF (340 ml) was added 60% NaH (140 mmol) in portions at 0° C. and the reaction mixture was stirred at 25° C. for 0.5 h. 2,2-Dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (93 mmol) was added at 0° C. and the mixture was allowed to warm to 25° C. and stirred for 21 h. The reaction was quenched with ethanol at 0° C. The solvent was evaporated under vacuum. Yield: 35 g (98% yield)
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([NH:25][C:26](=O)OC(C)(C)C)[CH2:11][N:12]([C:21](=[O:24])CBr)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:11][N:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[C:21](=[O:24])[CH2:26][NH:25]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC(COCc1ccccc1)CN(Cc1ccc(F)cc1)C(=O)CBr
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CNC(COCc2ccccc2)CN1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 2-(benzyloxy)-1-{[(bromoacetyl)(4-fluorobenzyl)amino]methyl}ethylcarbamate (2.79 g, 5.47 mmol) in CH2Cl2 (28 mL) was added trifluoroacetic acid (10 ml). The reaction was stirred at ambient temperature under inert atmosphere for 2 h and then concentrated in vacuo, azeotroping the residual oil with CHCl3. The resulting residue was dissolved in CH2Cl2 (100 mL) and treated with Hünig's base (10 mL). The solution was stirred at ambient temperature under inert atmosphere for 18 h. The solvent was removed in vacuo, and the remaining residue was partitioned between EtOAc and saturated aqueous NaHCO3 solution. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated in vacuo. Purification by silica gel chromatography (EtOAc to 10% MeOH/EtOAc) afforded the title compound as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.37-7.22 (m, 7H), 7.04-6.98 (m, 2H), 4.64 (d, J=14.8 Hz, 1H), 4.49-4.44 (m, 3H), 3.63 (dd, J=17.6, 41.2 Hz, 2H), 3.47 (dd, J=4.0, 9.6 Hz, 1H), 3.40 (dd, J=6.4, 9.2 Hz, 1H), 3.22-3.16 (m, 1H), 3.10-3.06 (m, 2H), 1.71 (br s, 1H). ES MS (M+1)=329.3.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C:6]1=[O:14])=[O:4].[OH-].[Na+].[Br:17][CH2:18][CH2:19][CH2:20]Br>C(O)C>[CH3:1][O:2][C:3]([C:5]1([CH2:20][CH2:19][CH2:18][Br:17])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C:6]1=[O:14])=[O:4]
Reactant: COC(=O)C1C(=O)Cc2ccccc21
Reactant: BrCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)C1(CCCBr)C(=O)Cc2ccccc21
Temperature: 40 °C
Reaction time: 48 h

Procedure:
A solution of 2-oxo-indan-1-carboxylic acid methyl ester (3.8 g) and NaOH (1 M in water, 20 mL) in ethanol (30 mL) is added dropwise to a solution of 1,3-dibromopropane (10 mL) in ethanol (20 mL) at room temperature. The solution is warmed to 40° C. and stirred at this temperature for 2 d. Then, the solution is concentrated under reduced pressure and ethyl acetate is added to the residue. The resulting mixture is washed with water and brine and dried (MgSO4). After removing the solvent, the residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 20:1->9:1) to give the title compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][NH:21][C:22]([C:24]2([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[OH:31]>[Pd]>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([CH2:20][NH:21][C:22]([C:24]2([NH2:29])[CH2:28][CH2:27][O:31][CH2:26][CH2:25]2)=[O:23])=[CH:18][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CO
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CNC(=O)C2(N)CCCC2)cc1
Agent: [Pd]
Product: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CNC(=O)C2(N)CCOCC2)cc1
Reaction time: 1 h

Procedure:
The product obtained in step C is dissolved in 30 ml of methanol. 400 mg of 10% palladium-on-charcoal are added and the mixture is hydrogenated at atmospheric pressure. After 1 hour, the catalyst is filtered off and the filtrate is then concentrated under vacuum. The residue is chromatographed on silica using an ethyl acetate/methanol/33% aqueous ammonia mixture (99/1/0.5; v/v/v) as the eluent to give 0.93 g of the expected product in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([O:46][CH3:47])=[C:4]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:19]=[C:20](/[CH:25]=[C:26](\[CH3:35])/[C:27]([NH:29][C:30]([CH3:34])([CH3:33])[CH2:31][OH:32])=[O:28])[CH:21]=[CH:22][C:23]=4[F:24])[CH:16]=3)[N:11](S(C3C=CC(C)=CC=3)(=O)=O)[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.O.C(=O)([O-])[O-].[K+].[K+]>CO>[F:1][C:2]1[C:3]([O:46][CH3:47])=[C:4]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([C:18]4[CH:19]=[C:20](/[CH:25]=[C:26](\[CH3:35])/[C:27]([NH:29][C:30]([CH3:33])([CH3:34])[CH2:31][OH:32])=[O:28])[CH:21]=[CH:22][C:23]=4[F:24])[CH:16]=3)[NH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COc1c(F)cc(F)cc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(/C=C(\C)C(=O)NC(C)(C)CO)ccc3F)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1c(F)cc(F)cc1-c1c[nH]c2ncc(-c3cc(/C=C(\C)C(=O)NC(C)(C)CO)ccc3F)cc12
Temperature: 60 °C

Procedure:
A solution of 163 (40 mg) was taken in methanol (7 mL) and water (3 mL) was added potassium carbonate (20 mg). The reaction was heated to 60° C. for overnight. The methanol was completely distilled and diluted with water. The organic phase was extracted with ethyl acetate (50 ml) twice. The organic layer was dried over sodium sulphate and filtered and concentrated to get the crude. The crude was triturated with hexane to afford the half white colour solid (E)-3-(3-(3-(3,5-difluoro-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-fluorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-2-methylacrylamide 164. MS-ES+486.19, 1H NMR (400 MHz, CDCl3): 9.6 (s, 1H), 8.31 (s, 1H), 8.05 (s, 1H), 7.52 (s, 1H) 7.44 (s, 3H), 7.22 (m, 1H), 7.1 (d, 1H), 6.8(m, 1H), 5.91 (s, 1H), 3.74 (s, 3H), 2.116 (s, 3H), 1.41 (s, 9H).
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[NH2:9][C:10]1[N:15]=[C:14]([C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][N:22]([C:26](OC4C=CC([N+]([O-])=O)=CC=4)=[O:27])[CH2:23]3)=[CH:18][CH:17]=2)[CH:13]=[C:12]([N:38]2[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]2)[N:11]=1>>[F:1][C:2]1([F:8])[CH2:7][CH2:6][N:5]([C:26]([N:22]2[CH2:21][CH2:20][C:19]3[C:24](=[CH:25][C:16]([C:14]4[CH:13]=[C:12]([N:38]5[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH2:43]5)[N:11]=[C:10]([NH2:9])[N:15]=4)=[CH:17][CH:18]=3)[CH2:23]2)=[O:27])[CH2:4][CH2:3]1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)Oc3ccc([N+](=O)[O-])cc3)CC4)nc(N)n2)CC1
Reactant: FC1(F)CCNCC1
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)N3CCC(F)(F)CC3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 103, Step 2 starting from 4,4-difluoropiperidine (Ryan Scientific, Cat. #1006) and 4-nitrophenyl 7-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3,4-dihydroisoquinoline-2(1H)-carboxylate. Analytic LCMS (M+H)+: m/z=472.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[F:24][C:25]1[CH:26]=[C:27]([OH:32])[CH:28]=[C:29]([F:31])[CH:30]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([O:32][C:27]3[CH:26]=[C:25]([F:24])[CH:30]=[C:29]([F:31])[CH:28]=3)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: Oc1cc(F)cc(F)c1
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2cc(Oc3cc(F)cc(F)c3)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (250 mg, 0.766 mmol) and 3,5-difluorophenol were reacted as starting materials at 150° C. for 6 hours and post-treatment was then conducted, whereby the title compound was obtained as colorless needles (315.0 mg, 98.0%). Melting point: 135.1-137.5° C. (ethyl acetate-diethyl ether-hexane).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9](=[O:12])[CH:8]=[CH:7]2.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9](=[O:12])[CH2:8][CH2:7]2
Reactant: Cc1cccc2ccc(=O)oc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cccc2c1OC(=O)CC2
Reaction time: 5 h
Yield: 88.4 %

Procedure:
To a solution of 8-Methyl coumarin (16.2 gm) in Ethyl acetate (160 ml), 10% w/w Palladium-charcoal (1.62 gm) was added. Hydrogenation was carried out for 5 hours at 55-60° C. in an autoclave at 240-250 psi. using Hydrogen gas. The reaction mixture was filtered through hyflow bed and distilled under vacuum to give a 14.5 gm of title compound as a white solid.
Reaction SMILES: N1C=CN=CC=1[CH:7](C)[C:8]([OH:10])=[O:9].[CH3:12][C:13]1[CH:18]=[N:17][CH:16]=[CH:15][N:14]=1.ClC(Cl)(Cl)C=O.[OH-]>>[N:14]1[CH:15]=[CH:16][N:17]=[CH:18][C:13]=1[CH:12]=[CH:7][C:8]([OH:10])=[O:9]
Reactant: Cc1cnccn1
Reactant: CC(C(=O)O)c1cnccn1
Agent: O=CC(Cl)(Cl)Cl
Agent: [OH-]
Product: O=C(O)C=Cc1cnccn1

Procedure:
Scheme M depicts a specific synthesis of a pyrazinyl propionic acid. Methylpyrazine anion is condensed with trichloroacetaldehyde followed by treatment with base (hydroxide), then acidification to produce 3-(-Pyrazinyl) Acrylic Acid 75. This acid is then catalytically hydrogenated over palladium on charcoal to yield 3-(2-Pyrazinyl)propionic Acid 76.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][N:12]=1)[C:7]([OH:9])=O)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:46]1[CH2:51][CH2:50][O:49][CH2:48][CH:47]1[C:52]1[C:60]2[S:59][C:58]([NH2:61])=[N:57][C:56]=2[C:55]([O:62][CH3:63])=[CH:54][CH:53]=1>C1COCC1.C(Cl)(Cl)Cl>[O:46]1[CH2:51][CH2:50][O:49][CH2:48][CH:47]1[C:52]1[C:60]2[S:59][C:58]([NH:61][C:7](=[O:9])[C:6]3[CH:10]=[CH:11][N:12]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)=[N:57][C:56]=2[C:55]([O:62][CH3:63])=[CH:54][CH:53]=1
Reactant: CCOc1cc(C(=O)O)ccn1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOc1cc(C(=O)Nc2nc3c(OC)ccc(C4COCCO4)c3s2)ccn1

Procedure:
From 2-ethoxy-isonicotinic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+31.7° (c=0.61, CHCl3), ES-MS m/e (%): 416 (M+H+, 100).
Reaction SMILES: [C:1]([N:6]=[C:7]=[O:8])(=[O:5])[C:2]([CH3:4])=[CH2:3].[F:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12]>ClC(Cl)C.C(Cl)(Cl)Cl>[C:1]([NH:6][C:7]([NH:12][C:11]1[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=1[F:9])=[O:8])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: Nc1ccccc1F
Reactant: C=C(C)C(=O)N=C=O
Solvent: CC(Cl)Cl
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)NC(=O)Nc1ccccc1F

Procedure:
To methacryloyl isocyanate (5.55 g; 50 mmol) in dichloroethane (15 ml), a solution of o-fluoroaniline (5.55 g; 50 mmol) in chloroform (30 ml) was dropwise added. After completion of the addition, the precipitated crystals were collected by filtration. From the filtrate, the solvent was removed by evaporation under reduced pressure. The residue and the crystals were combined together and recrystallized from benzene to give N-methacryloyl-N'-o-fluorophenylurea as colorless needles. M.P., 155°-157° C.
Reaction SMILES: C1[C@H](N)[C@@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2N)[C@H]([O:20][C@@H:21]2[O:25][C@H:24](CO)[C@@H:23](O[C@H]3O[C@@H](CN)[C@@H](O)[C@H](O)[C@H]3N)[C@H:22]2[OH:40])[C@@H](O)[C@@H]1N.OS(O)(=O)=O.[CH2:48]([O:55][C:56]([NH:58][C:59]([N:71]1C=CC=N1)=[N:60][C:61]([O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)=[O:62])=[O:57])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:56]([N:58]([CH2:24][CH2:23][C@H:22]([OH:40])[C:21]([OH:25])=[O:20])[C:59]([NH2:71])=[N:60][C:61]([O:63][CH2:64][C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1)=[O:62])([O:55][CH2:48][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)=[O:57]
Reactant: O=C(N=C(NC(=O)OCc1ccccc1)n1cccn1)OCc1ccccc1
Reactant: NC[C@@H]1O[C@H](O[C@H]2[C@@H](O)[C@H](O[C@@H]3[C@@H](O)[C@H](N)C[C@H](N)[C@H]3O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3N)O[C@@H]2CO)[C@H](N)[C@@H](O)[C@@H]1O
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=NC(=O)OCc1ccccc1)N(CC[C@H](O)C(=O)O)C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 2(S)-hydroxy-4-amino-butyric acid (1, 0.059 g, 0.50 mmol) in DMF (2 ml) was added N,N′-bis(benzyloxycarbonyl)-1H-pyrazole-1-carboxamidine (0.26 g, 0.70 mmol) followed by DIPEA (0.87 mL, 4.99 mmol) and the reaction was heated to 80° C. and stirred overnight. The crude mixture was purified on a 2-inch reverse-phase HPLC column to yield N,N′-bis-Cbz-2(S)-hydroxy-4-guanidino-butyric acid (2): MS: m/z (M+H)+ calc. 430.15, obs. 430.1.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH:20]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:16][CH2:15]1)[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.FC(F)(F)C(O)=O.[ClH:43]>C(Cl)Cl.CCOCC>[ClH:43].[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH:20]([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[N:17]2[CH2:16][CH2:15][N:14]([CH2:13][C@@H:8]([NH2:7])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:19][CH2:18]2)=[CH:22][CH:23]=1
Reactant: CC(C)C[C@@H](CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](N)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reaction time: 3 h

Procedure:
(S)-(1-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-1-ylmethyl}-3-methyl-butyl)carbamic acid tert-butyl ester (0.225 g, 0.461 mmol, Example 35) was dissolved in CH2Cl2 (4 mL) under nitrogen at ambient temperature. To this solution was added trifluoroacetic acid (0.5 mL). The resulting reaction mixture was stirred for 3 hours, then concentrated in vacuo. The viscous pale-amber oil obtained was dissolved in 5 mL of ether and treated with 3.3 mL of saturated ethereal HCl. The resulting white precipitate was triturated with 3:1 EtOAc/2,2,4-trimethylpentane, and collected via filtration. The filtrate was concentrated in vacuo affording a viscous amber oil (189 mg) which was used in the subsequent reaction without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1)([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([S:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: Clc1ccnc2ccccc12
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Sc2ccnc3ccccc23)cc1
Yield: 53.7 %

Procedure:
4-Chloroquinoline (32.3 mmoles, 5.2 g),4-nitrothiophenol (32.3 moles, 5.0 g) and potassium carbonate (32.3 moles, 4.46 g) were stirred at room temperature in 500 ml of ethanol for 16 hr. The reaction mixture was then concentrated, ethyl acetate was added and the solution washed with water, dried over sodium sulfate and concentrated. The product was purified by HPLC over silica gel eluted with 20-40% ethyl acetate/hexane to yield 4-(4-nitrophenylthio)quinoline 4.9 g, 54%. Mass Spec (FD) 282. Calculated for C15H10N2O2S: C, 63.82 H, 3.57 N, 9.92. Found: C, 65.09; H, 3.81; N, 10.02.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1>O>[CH:10]1[CH:11]=[C:12]2[C:13]([OH:15])=[C:14]3[C:5](=[C:6]([OH:16])[C:7]2=[CH:8][CH:9]=1)[CH:4]=[CH:3][CH:2]=[CH:1]3
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Solvent: O
Product: Oc1c2ccccc2c(O)c2ccccc12

Procedure:
As is known, hydrogen peroxide is produced currently by the so-called anthraquinone method involving the reaction of autoxidation of anthraquinone. In the anthraquinone method, namely, a 2-alkyl anthraquinone is hydrogenated in a water-insoluble organic solvent in the presence of a hydrogenation catalyst to give a corresponding anthrahydroquinone compound which is, after being freed from the catalyst by filtration, oxidized with oxygen or air to regenerate the starting anthraquinone compound with concurrent formation of hydrogen peroxide which is extracted with water to give an aqueous solution of hydrogen peroxide. The thus obtained aqueous solution of hydrogen peroxide contains considerable amounts of organic materials as impurities including the anthraquinone compounds and organic solvents as well as degradation products thereof so that it is a usual practice that the organic impurities in the aqueous hydrogen peroxide solution are removed by extraction with a water-immiscible organic solvent to give a primarily purified aqueous solution of hydrogen peroxide, referred to as a crude hydrogen peroxide solution hereinafter, containing decreased amounts of organic impurities. The content of hydrogen peroxide in a crude hydrogen peroxide solution is usually in the range from 15 to 40% by weight so that the solution in most cases must be enriched relative to the content of hydrogen peroxide, even by setting aside the problem relative to the content of impurities, since the aqueous hydrogen peroxide solution industrially required should have a content of hydrogen peroxide in the range from 30 to 70% by weight.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].CN(C=O)C.[H-].[Na+].Cl[CH2:20][O:21][CH2:22][CH3:23]>O>[N+:1]([C:4]1[CH:10]=[CH:9][C:8]([S:11][CH2:20][O:21][CH2:22][CH3:23])=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: CCOCCl
Reactant: Nc1cc(S)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCSc1ccc([N+](=O)[O-])c(N)c1
Reaction time: 0.5 h

Procedure:
A solution of 3.4 g. of 2-nitro-5-mercaptoaniline in 20 ml. of DMF is treated with 0.5 g. of 100% sodium hydride, and 2.2 g. of chloromethyl-ethyl ether is added to the solution. After 30 minutes at 20°-25° C, the solution is diluted with water and extracted with chloroform. Removal of the chloroform leaves 2-nitro-5-(ethoxymethylthio) aniline as an oil.
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][C:8](=O)[CH2:7][C:6](=[O:11])[CH2:5]1)([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+:16]>>[NH2:16][C:8]1[CH2:9][CH:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][C:6](=[O:11])[CH:7]=1
Reactant: CC(C)C1CC(=O)CC(=O)C1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: CC(C)C1CC(=O)C=C(N)C1

Procedure:
In analogy to (Baraldi, P. G.; Simoni, D.; Manfredini, S.; Synthesis 1983, (11) 902-903) 5-isopropylcyclohexane-1,3-dione was reacted with ammonium acetate to give the title compound as a colorless solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([O:18][CH2:19][CH3:20])=[N:9][N:10](C(OC(C)(C)C)=O)[C:4]=2[CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C@H:28]([NH:30][C:31]([NH2:33])=[O:32])[CH3:29])=[CH:24][CH:23]=1.CC(P(C(C)(C)C)C1N(C2C(C3C=CC=CC=3)=NN(C3C=CC=CC=3)C=2C2C=CC=CC=2)N=CC=1)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:19]([O:18][C:8]1[C:5]2[CH:6]=[N:7][C:2]([NH:33][C:31]([NH:30][C@@H:28]([C:25]3[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=3)[CH3:29])=[O:32])=[CH:3][C:4]=2[NH:10][N:9]=1)[CH3:20]
Reactant: C[C@@H](NC(N)=O)c1ccc(F)cc1
Reactant: CCOc1nn(C(=O)OC(C)(C)C)c2cc(Cl)ncc12
Agent: [Pd]
Agent: CC(C)(C)P(c1ccnn1-c1c(-c2ccccc2)nn(-c2ccccc2)c1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: CCOc1n[nH]c2cc(NC(=O)N[C@H](C)c3ccc(F)cc3)ncc12
Temperature: 85 °C
Reaction time: 18 h

Procedure:
tert-Butyl 6-chloro-3-ethoxy-1H-pyrazolo[4,3-c]pyridine-1-carboxylate (77 mg, 0.259 mmol), (R)-1-(1-(4-fluorophenyl)ethyl)urea (Intermediate 15B; 60 mg, 0.329 mmol), bippyphos (15.6 mg, 0.031 mmol), Pd2(dba)3 (9.6 mg, 10.48 μmol), and tripotassium phosphate (82 mg, 0.388 mmol) were taken up in DME (1.3 mL) in a 5 mL microwave vial. The vial was evacuated and back-filled with N2 (×3) and the reaction stirred at 85° C. for 18 h. Room temperature was attained, the reaction mixture was filtered through Celite, eluting with MeOH, and the filtrate was concentrated in vacuo. The residue was dissolved in TFA (2 mL) and the solution stirred at room temperature for 3 h. The solvent was removed in vacuo, saturated NaHCO3 was added, and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (0-100% EtOAc-DCM) gave (R)-1-(3-ethoxy-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-(4-fluorophenyl)ethyl)urea. MS ESI calc'd. For C17H18FN5O2 [M+1]+ 344. found 344. 1H NMR (500 MHz, DMSO-d6) δ 1H NMR (500 MHz, DMSO-d6) δ 11.94 (s, 1H), 8.91 (s, 1H), 8.53 (s, 1H), 7.76 (br s, 1H), 7.46 (s, 1H), 7.39-7.33 (m, 2H), 7.15 (t, J=8.8 Hz, 2H), 4.89-4.82 (m, 1H), 4.33 (q, J=7.0 Hz, 2H), 1.41-1.34 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.CO[C:13](OC)([N:15](C)C)[CH3:14].Cl.NO.C([O-])([O-])=O.[K+].[K+]>[OH-].[Na+].C(Cl)Cl.CC(O)=O.O1CCOCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:7][N:15]=[C:13]([CH3:14])[N:8]=2)=[CH:4][CH:3]=1
Reactant: COC(C)(OC)N(C)C
Reactant: NC(=O)c1ccc(Br)cc1
Agent: Cl
Agent: NO
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1noc(-c2ccc(Br)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Bromobenzamide (5.3 g) and N,N-dimethylacetamide dimethylacetal (35 ml) were heated together at 125° C. for 2 h. The reaction was allowed to cool to rt and the liquid evaporated to give a pale yellow solid. Hydroxylamine hydrochloride (2.2 g) in 1 N NaOH solution (36 ml) was added, followed by dioxane (36 ml) then AcOH (48 ml). The reaction mixture was stirred at rt for 30 min then heated at 90° C. for 3 h. The reaction was allowed to cool to rt and saturated aqueous K2CO3 solution (100 ml) was added followed by DCM (200 ml) before filtering. The organic phase was separated from the mixture, then saturated brine (100 ml) was added and the aqueous phase was extracted into EtOAc (200 ml). The combined organic phases were dried (Na2SO4) and evaporated to give a brown solid. The crude product was purified by column chromatography (silica gel, step gradient 10-50% EtOAc in hexanes) to give the title compound (D14) as a white solid (2.9 g). LCMS electrospray (+ve) 239, 241 (MH+).