Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=4[F:24])[CH:15]=3)[N:10]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)[N:9]=2)[CH:5]=[N:4][CH:3]=1.[C:31]([N:38]1[CH2:42][CH2:41][C@@H:40]([NH2:43])[CH2:39]1)([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].CC(C)([O-])C.[Na+]>O1CCOCC1.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[F:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:17]=1[C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[N:9]=[C:8]2[C:6]1[N:7]=[C:2]([NH:43][C@@H:40]2[CH2:41][CH2:42][N:38]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:39]2)[CH:3]=[N:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: Fc1cccc(F)c1-c1ccc2c(c1)c(-c1cncc(Cl)n1)nn2C1CCCCO1
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2cncc(-c3nn(C4CCCCO4)c4ccc(-c5c(F)cccc5F)cc34)n2)C1
Temperature: 85 °C
Yield: 82.9 %

Procedure:
A glass microwave reaction vessel was charged with 3-(6-chloropyrazin-2-yl)-5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (250 mg, 0.586 mmol) and (R)-(+)-1-boc-3-aminopyrrolidine (149 μL, 0.879 mmol, CNH technologies) in p-dioxane (2.5 mL) followed by chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (BrettPhos precatalyst) (23.39 mg, 0.029 mmol), sodium tert-butoxide (143 μL, 1.171 mmol) and BrettPhos precatalyst (15.72 mg, 0.029 mmol). The reaction mixture was stirred and heated in an oil bath at 85° C. for 2 h, and then solvent was removed. The residue was purified by silica gel chromatography (eluting with 5-30% EtOAc in DCM with 1% MeOH) to give (3R)-tert-butyl 3-(6-(5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-ylamino)pyrrolidine-1-carboxylate (280 mg, 83% yield). MS (ESI, pos. ion) m/z: 577 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([Br:18])[N:15]=[C:14](Br)[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:20][NH2:21]>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([NH:21][CH3:20])[N:15]=[C:16]([Br:18])[CH:17]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CN
Reactant: Nc1ccc(S(=O)(=O)Nc2cc(Br)nc(Br)c2)cc1
Product: CNc1cc(NS(=O)(=O)c2ccc(N)cc2)cc(Br)n1
Yield: 88 %

Procedure:
0.81 g (0.002 mol) of 4-amino-N-(2,6-dibromo-pyridin-4-yl)-benzenesulfonamide was stirred in 35 ml of liquid methylamine in an autoclave at 130° C. for 44 hours. The methylamine was left to evaporate, the residue was dissolved in ethanol, treated with 2 g of silica gel, concentrated and the residue was chromatographed on silica gel, firstly with ethyl acetate/hexane 1:2, then with pure ethyl acetate. There was obtained 0.63 g (88%) of 4-amino-N-(2-bromo-6-methylamino-pyridin-4-yl)-benzenesulfonamide as a beige foam. 0.33 g (0.00092 mol) of this was dissolved in 10 ml of methanol, treated with 5 ml of 2M HCl in methanol, concentrated and again treated with 4 ml of methanol. The precipitate obtained was filtered off under suction, rinsed with a small amount of methanol and dried in a high vacuum. There was obtained 0.27 g (69%) of 4-amino-N-(2-bromo-6-methylamino-pyridin-4-yl)-benzenesulfonamide hydrochloride as white crystals; m.p.: 226-228° C. (dec.).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:7][C:8]1[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=1[O:10][CH2:11][C:12](O)=[O:13])[CH3:6]>>[CH2:5]([O:7][C:8]1[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=1[O:10][CH2:11][C:12]([Cl:3])=[O:13])[CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CCOc1ccccc1OCC(=O)O
Product: CCOc1ccccc1OCC(=O)Cl

Procedure:
1.30 g (11 mmol) of thionyl chloride was added to 1.96 g (10 mmol, 1.0 eq.) of (2-ethoxy-phenoxy)acetic acid. The mixture was heated under reflux for 30 minutes and distilled under reduced pressure to obtain (2-ethoxy-phenoxy)acetyl chloride. 20 ml of THF and 2.78 ml (20 mmol, 2.0 eq.) of triethylamine were added to 2.44 g (10 mmol, 1.0 eq.) of (R)-(-)-5-[(2-amino-2-methyl)ethyl]-2-methoxybenzene sulfonamide and the reaction solution was cooled down to 0° C. The obtained (2-ethoxy-phenoxy)acetyl chloride was added dropwise thereto and the whole mixture was stirred for 1 hour. The formed solids were filtered, and the filtrate was distilled under reduced pressure and extracted with 40 ml of ethyl acetate. Subsequently, the extract was washed with 1 N HCl, a saturated aqueous solution of sodium bicarbonate and brine, and dried over magnesium sulfate and then, filtered. The filtrate was distilled under reduced pressure to obtain 3.80 g (yield: 90%) of 2-(2-ethoxy-phenoxy)-N-[2-(4-methoxy-3-sulfamoyl-phenyl)-1-methyl-ethyl]-acetamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:18])=[CH:20][CH:21]=1)([O-:12])=[O:11]
Reactant: COc1cccc(N)c1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Product: COc1cccc(NC(=O)c2ccc([N+](=O)[O-])cc2)c1
Yield: 93 %

Procedure:
Using m-anisidine (2.50 g, 15.0 mmol) and 4-nitrobenzoic acid (2.03 g, 16.5 mmol), the procedure of Reference Example 16 was repeated to obtain 3.80 g (93.2%) of the title compound in the form of light yellow needle crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[C:16]3[C@H:15]4[CH2:17][C@H:14]4[CH2:13][C:12]=3[C:11]([C:18](O)=[O:19])=[N:10]2)[CH:4]=1)#[N:2].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:53][C@@H:54]([CH2:57][C:58]([F:61])([F:60])[F:59])[CH2:55][OH:56]>CN(C=O)C>[F:59][C:58]([F:61])([F:60])[CH2:57][C@H:54]([NH:53][C:18]([C:11]1[C:12]2[CH2:13][C@@H:14]3[CH2:17][C@@H:15]3[C:16]=2[N:9]([C:5]2[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][N:6]=2)[N:10]=1)=[O:19])[CH2:55][OH:56]
Reactant: N#Cc1ccnc(-n2nc(C(=O)O)c3c2[C@H]2C[C@H]2C3)c1
Reactant: N[C@H](CO)CC(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1ccnc(-n2nc(C(=O)N[C@H](CO)CC(F)(F)F)c3c2[C@H]2C[C@H]2C3)c1
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 77.9 %

Procedure:
To a solution of (1aS,5aS)-2-(4-cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (75 mg, 0.282 mmol) and triethylamine (0.118 mL, 0.845 mmol) in DMF (1 mL) was added HATU (118 mg, 0.310 mmol). The reaction was stirred at 23° C., for 5 min, then was added (S)-2-amino-4,4,4-trifluorobutan-1-ol hydrochloride (55.6 mg, 0.310 mmol). The reaction was stirred at 23° C. for 30 min, then concentrated. The residue was purified by silica gel flash chromatography to give the title compound (86 mg) as a white solid. LCMS m/z=392.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.47 (td, J=4.7, 3.2 Hz, 1H), 1.27 (td, J=8.1, 4.8 Hz, 1H), 2.26-2.32 (m, 1H), 2.54-2.69 (m, 3H), 2.77-2.82 (m, 1H), 2.93 (d, J=16.8 Hz, 1H), 3.01 (dd, J=16.6, 6.1 Hz, 1H), 3.88 (d, J=2.9 Hz, 2H), 4.33-4.41 (m, 1H), 7.23 (d, J=8.2 Hz, 1H), 7.41 (dd, J=5.1, 1.4 Hz, 1H), 8.17 (t, J=0.8 Hz, 1H), 8.62 (dd, J=5.1, 0.6 Hz, 1H).
Reaction SMILES: C1(=O)N([O:6][C:7]([CH2:9][CH2:10][C:11]2[C:16](=[O:17])[N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH3:35])=[O:26])[CH:19]=3)[C:14]3[N:36]=[CH:37][CH:38]=[CH:39][C:13]=3[N:12]=2)=O)C(=O)CC1.Cl.[CH3:43][NH:44][CH3:45]>O1CCOCC1.O.C(N(CC)CC)C.C(OCC)(=O)C>[CH3:43][N:44]([CH3:45])[C:7]([CH2:9][CH2:10][C:11]1[C:16](=[O:17])[N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[O:26])[CH:19]=2)[C:14]2[N:36]=[CH:37][CH:38]=[CH:39][C:13]=2[N:12]=1)=[O:6]
Reactant: CNC
Reactant: COc1ccccc1NC(=O)Nc1cccc(-n2c(=O)c(CCC(=O)ON3C(=O)CCC3=O)nc3cccnc32)c1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccccc1NC(=O)Nc1cccc(-n2c(=O)c(CCC(=O)N(C)C)nc3cccnc32)c1
Reaction time: 18 h

Procedure:
To a solution of 2-[2-succinimidooxycarbonylethyl]-4-[3-[3-(2-methoxyphenyl)ureido]phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (0.28 g) in dioxane was added a solution of dimethylamine hydrochloride (81 mg) in water and triethylamine (101 mg). The mixture was stirred for 18 hours, diluted with ethyl acetate, washed with water. After removal of the solvents, crude residue was crystallized from ethanol to give 2-[2-(N,N-dimethylcarbamoyl)ethyl]-3-oxo-4-[3-[3-(2-methoxyphenyl)ureido]phenyl]-3,4-dihydropyrido[2,3-b]pyrazine.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][C@H:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[S:26][CH:27]=[C:28]([CH2:30][CH3:31])[N:29]=4)=[CH:21][C:20]=3[CH2:32][CH2:33][CH3:34])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)C.O[Li].O>C1COCC1.O>[CH2:30]([C:28]1[N:29]=[C:25]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH2:16][O:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[C@H:6]([CH2:5][C:4]([OH:35])=[O:3])[CH2:7][CH2:8]4)=[C:20]([CH2:32][CH2:33][CH3:34])[CH:21]=2)[S:26][CH:27]=1)[CH3:31]
Reactant: CCCc1cc(-c2nc(CC)cs2)ccc1OCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CCCc1cc(-c2nc(CC)cs2)ccc1OCCOc1ccc2c(c1)CC[C@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 11.8 %

Procedure:
To a solution of ethyl((1S)-5-{2-[4-4-ethyl-1,3-thiazol-2-yl)-2-propylphenoxy]ethoxy}-2,3-dihydro-1H-inden-1-yl)acetate (18 mg, 0.04 mmol) (Example 35) in THF (1.2 mL), was added a solution of LiOH.H2O (5 mg, 0.11 mmol) in H2O (0.4 mL). The mixture was stirred for 12 h at rt. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in a small volume of water. Then, HCl (1 N aqueous solution) was added until the solution was below pH 3. The aqueous layer was extracted with excess EtOAc, and the organic layer was dried, filtered and then concentrated to give the crude product. The residue was purified by HPLC (C18 reverse phase column, using 0-80% CH3CN in water) to give 2.2 mg (13%) of the title compound as a white solid. LC-MS: RT 3.78 min; (M+H)+: 466.4.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:13]([O:16]C)=[N:14][N:15]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[CH:6]=2.C(N(CC)CC)C.[S:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[NH:34][CH2:35][CH2:36][NH2:37]>CN(C=O)C.CC(O)C.C(Cl)Cl.Br.CC(O)=O>[S:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[NH:34][CH2:35][CH2:36][NH:37][C:2]1[C:3]2[N:4]([C:13](=[O:16])[NH:14][N:15]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[CH:6]=2
Reactant: NCCNc1nc2ccccc2s1
Reactant: COc1nnc2c(Cl)nc3ccc(Cl)cc3n12
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1[nH]nc2c(NCCNc3nc4ccccc4s3)nc3ccc(Cl)cc3n12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 100 mg of 4,8-dichloro-1-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline and 109 mg of triethylamine in DMF (2.0 mL) was added 86 mg of N1-benzothiazol-2-yl-ethane-1,2-diamine. This solution was stirred at room temperature for 18 hrs. and then diluted with 10% IPA/methylene chloride, and washed with water and brine. The extracts were dried over sodium sulfate, filtered, and concentrated. The residue was separated by silica gel chromatography to provide a yellow solid. This solid was dissolved in a 1:1.5 mixture of 48% HBr/AcOH and refluxed for 2 hrs. The reaction mixture was concentrated and the residue was triturated with IPE to provide the hydrobromide salt of the title compound as a yellow solid. MS (M+H)+=412.2.
Reaction SMILES: [OH:1]/[N:2]=[CH:3]/[C:4]1[C:12]2[N:8]([CH:9]=[CH:10][CH:11]=2)[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C.[Cl:48][C:49]1[CH:54]=[C:53]([C:55]([C:57]([F:60])([F:59])[F:58])=[CH2:56])[CH:52]=[C:51]([Cl:61])[CH:50]=1>C1COCC1>[Cl:48][C:49]1[CH:54]=[C:53]([C:55]2([C:57]([F:60])([F:58])[F:59])[O:1][N:2]=[C:3]([C:4]3[C:12]4[N:8]([CH:9]=[CH:10][CH:11]=4)[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=3)[CH2:56]2)[CH:52]=[C:51]([Cl:61])[CH:50]=1
Reactant: CCOC(=O)c1ccc(/C=N/O)c2cccn12
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Solvent: Ic1ccccc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2cccn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.1 %

Procedure:
A solution of crude (E)-ethyl 8-((hydroxyimino)methyl)indolizine-5-carboxylate (0.46 mmol) in THF (5 mL) was added slowly to a stirred solution of iodobenzene diacetate, (PhI(OAc)2, DIB, 296 mg, 0.92 mmol) and 1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (222 mg, 0.92 mmol) in THF (10 mL) at rt. The mixture was stirred for 1 h at rt. The solvent was removed under reduced pressure and the crude product was purified by prep-TLC and then combiflash to give ethyl 8-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-5-carboxylate (50 mg, yield 23% over 2 steps). 1H NMR (400 MHz, DMSO-d6): δ 8.66 (t, J=2.0 Hz, 1H), 7.84 (t, J=2.0 Hz, 1H), 7.68-7.71 (m, 3H), 7.25-7.27 (m, 2H), 7.06 (m, 1H), 4.43-4.56 (m, 4H), 1.41 (t, J=2.0 Hz, 3H) ppm; MS: m/z=471.7 (M+1, ESI+).
Reaction SMILES: [CH:1]1([CH:7]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[O:33])=[CH:28][CH:27]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[O:10][C:9]=2[CH2:23][CH3:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.CCCCCC>[CH:1]1([CH:7]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][CH:31]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=3)[O:10][C:9]=2[CH2:23][CH3:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2cc(-c3ccc(C(F)(F)F)cc3)oc2CC)C2CCCCC2)cc1
Solvent: CCCCCC
Solvent: CCO
Product: CCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
Ethyl 3-[({4-[(cyclohexyl{2-ethyl-5-[4-(trifluoromethyl)phenyl]furan-3-yl}methyl)amino]phenyl}carbonyl)(methyl)amino]propanoate (880 mg) which is a synthetic intermediate in Example 10 was dissolved in ethanol-hexane (1:1, volume ratio), and the solution was subjected to HPLC using CHIRALPAK AD (50 mmID×500 mL, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.) and eluted with ethanol-hexane (1:1, volume ratio) as mobile phase at 30° C., a flow rate 60 mL/min. The fractions showing a peak with retention time 29 min were collected, and concentrated. The obtained amorphous compound (355 mg) was dissolved in ethanol (5 mL) and tetrahydrofuran (5 mL), 1N lithium hydroxide (2 mL) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (20 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (336 mg, 99%).
Reaction SMILES: [CH3:1][N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.[NH2:14][C:15]1N=C[NH:17][N:16]=1.C(=O)(O)[O-].[Na+].[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2]>C(Cl)Cl.CCCCCC.C(O)(=O)C>[C:7]1([C:5]2[N:17]3[N:16]=[CH:15][N:14]=[C:1]3[N:2]=[CH:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)C=CC(=O)c1ccccc1
Reactant: Nc1nc[nH]n1
Agent: O=C([O-])O
Agent: [Mg+2]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCCCCC
Product: c1ccc(-c2ccnc3ncnn23)cc1

Procedure:
A mixture of 5.25 g. of 3-dimethylaminoacrylophenone and 2.52 g. of 3-amino-1,2,4-triazole in 25 ml. of glacial acetic acid is refluxed for 4 hours. Evaporation gives a solid which is treated with a saturated sodium bicarbonate solution and dissolved in methylene chloride. This solution is passed through a short column of a hydrous magnesium silicate. Addition of hexane to a refluxing solution of the eluent gives crystals of the desired compound, m.p. 143°-144° C. K. Shirakawa, Yakugaku Zasshi 80, 956 (1960) cites melting point 140° C. for the compound assigned this structure but prepared by a different route.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1>C(#N)C.O>[N:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:22]=1[CH2:21][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: CCOC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 80 °C
Yield: 118.2 %

Procedure:
To a stirred solution of ethyl 2-(4-hydroxyphenyl)acetate (10 g, 0.05 mol) in acetonitrile (150 mL) were added K2CO3 (23 g, 0.16 mol) and 2-(chloromethyl)quinoline (14.2 g, 0.06 mol) under an inert atmosphere. The reaction mixture was then heated at 80° C. for 16 h, diluted with water (50 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford ethyl 2-(4-(quinolin-2-ylmethoxy)phenyl)acetate (19 g, 95%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.O.Cl.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([NH2:1])=[CH:16][CH:15]=2)=[CH:13][CH:12]=1
Reactant: Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1ccc(Cc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 75.6 %

Procedure:
A suspension of 4.27 g (18.4 mmols) of 4-amino-4' chloro-benzophenone and 8.54 g of zinc amalgam in 80 ml of toluene containing 4 ml of water was heated to reflux. 1 ml of concentrated hydrochloric acid were added over 90 minutes. After 22 hours, the mixture was allowed to cool to room temperature and 100 ml of ethyl acetate and 2×100 ml of water were added. The layers were separated and the aqueous phase was extracted with 50 ml of ethyl acetate. The combined organics were washed twice with 100 ml of water and 50 ml of brine, dried over MgSO4, filtered and evaporated to obtain 3.03 g of orange oil. Flash chromatography (20-35% ethyl acetate/pet ether eluent) yielded the above mentioned product as an orange liquid 915 mg (24.6% yield). 1H nmr (CDCl3) δ3.58 (2H, br s) , 3.82 (2H, s), 6.62 (2H, d), 6.94 (2H, d), 7.08 (2H, d), 7.22 (2H, d)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[CH2:19][CH2:20][S:21](Cl)(=[O:23])=[O:22].O>ClCCl>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][S:21]([CH:20]=[CH2:19])(=[O:23])=[O:22])=[CH:5][CH:4]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=S(=O)(Cl)CCCl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C=CS(=O)(=O)NCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.4 %

Procedure:
A cold solution of 4-methoxybenzylamine (2 g) and triethylamine (2.8 ml) in dry dichloromethane (20 ml) at -78° was transferred under nitrogen to a solution of 2-chloroethanesulphonyl chloride (4.9 g) in dry dichloromethane (20 ml) at -78°. The mixture was stirred for 4 h whilst warming to room temperature and then refrigerated overnight. Water (ca 100 ml) was added and the organic layer separated. This was washed with hydrochloric acid (2N, 50 ml), water (50 ml) and brine (50 ml), dried (MgSO4) and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane) to give the title compound as a powder (2 g) m.p. 68°-69°.
Reaction SMILES: Cl.N[CH2:3][CH2:4][SH:5].C1(C)C=CC=CC=1.C(N(CC)CC)C.[CH3:20][C:21]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][C:22]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31](=[N:34][O:35][CH3:36])[C:32]#[N:33]>O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C.O>[CH3:36][O:35][N:34]=[C:31]([C:32]1[S:5][CH2:4][CH2:3][N:33]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][O:23][C:22]1[CH:37]=[C:38]([CH3:41])[CH:39]=[CH:40][C:21]=1[CH3:20]
Reactant: CON=C(C#N)c1ccccc1COc1cc(C)ccc1C
Reactant: NCCS
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: CON=C(C1=NCCS1)c1ccccc1COc1cc(C)ccc1C
Yield: 79 %

Procedure:
2-Aminoethanethiol hydrochloride (2.80 g, 24.6 mmol), zinc acetate dihydrate (600 mg, 2.7 mmol), toluene (12 ml) and triethylamine (3.12 g, 30.8 mmol) were added to 2-(2,5-dimethylphenoxymethyl)-α-methoxyiminophenylacetonitrile (6.00 g, 20.4 mmol), and the mixture was stirred under reflux for 14 hours. After completion of the reaction, water (100 ml) was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2,5-dimethylphenoxymethyl)phenyl 2-thiazolin-2-yl ketone O-methyloxime (5.71 g, 79.0%) as crystals.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH3:35][C:36]1[C:44]2[C:43]([N:45]3[CH2:50][CH2:49][CH:48]([NH2:51])[CH2:47][CH2:46]3)=[N:42][CH:41]=[N:40][C:39]=2[NH:38][CH:37]=1>C(Cl)Cl>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:51][CH:48]2[CH2:47][CH2:46][N:45]([C:43]3[N:42]=[CH:41][NH:40][C:39]4=[N:38][CH:37]=[C:36]([CH3:35])[C:44]=34)[CH2:50][CH2:49]2)=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1c[nH]c2ncnc(N3CCC(N)CC3)c12
Reactant: Cc1ccc(C(=O)O)cn1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)NC2CCN(c3nc[nH]c4ncc(C)c3-4)CC2)cn1
Reaction time: 0.17 h

Procedure:
To a mixture of 6-methyl-3-pyridinecarboxylic acid (46.1 mg, 0.336 mmol), EDC (68.7 mg, 0.359 mmol), HOBt (54.9 mg, 0.359 mmol) and DIPEA (0.098 mL, 0.560 mmol) in DCM (1 mL), prestirred for 10 minutes, was added 1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine hydrochloride D11 (60 mg) and the mixture stirred for 18 hours. The mixture was partitioned between DCM (4 mL) and aqueous sodium bicarbonate (4 mL) and the aqueous phase was extracted with further DCM (4 mL). The combined organic fractions were concentrated in vacuo and purified by MDAP. The solvent was then removed in vacuo from the product containing fractions, to afford E22 (14 mg), 1H NMR (d6-DMSO) δ 11.53 (1H, s), 8.90 (1H, s), 8.47 (1H, d), 8.22 (1H, s), 8.10 (1H, d), 7.35 (1H, d), 7.07 (1H, s), 4.08 (1H, m), 4.02 (2H, d), 3.95 (2H, t), 2.47 (3H, s), 2.37 (3H, s), 1.95 (2H, d), 1.73 (2H, ddd), MS(ES+) 351 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][C:12]=2[N+:20]([O-:22])=[O:21])=[O:9])=[CH:4][CH:3]=1.[CH3:23][O-].[Na+].IC>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][C:12]=2[N+:20]([O-:22])=[O:21])[CH3:23])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOc1ccc(NC(=O)c2ccc(Cl)nc2)c([N+](=O)[O-])c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: CCOc1ccc(N(C)C(=O)c2ccc(Cl)nc2)c([N+](=O)[O-])c1
Reaction time: 0.17 h

Procedure:
To a solution of 6-chloro-N-(4-ethoxy-2-nitrophenyl)-3-pyridinecarboxamide (50 mg, 0.155 mmol) in DMF (2 ml) was added sodium methoxide (12 mg, 0.222 mmol) in DMF (1 ml) and the reaction mixture was stirred for 10 min. To the mixture was added iodomethane (22 mg, 0.155 mmol) slowly and the mixture was stirred for at room temperature for 3 h. It was diluted with ethyl acetate and washed with water and brine, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by column chromatography to yield the titled compound as a light brown liquid. 1H NMR (CDCl3): 8.17 (d, J=2.1, 1H), 7.68-7.65 (m, 1H), 7.35 (d, J=2.7, 1H), 7.21 (t, J=7.8, 2H), 7.10-7.06 (m, 1H), 4.08-4.01 (m, 2H), 3.40 (s, 3H), 1.44 (t, J=6.9, 3H).