Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]([CH2:14][CH:15]1[O:20][CH2:19][CH2:18][N:17](CC2C=CC=CC=2)[CH2:16]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][CH3:13])(=[O:3])[CH3:2].Cl.C(N(CC1OCCN(CC2C=CC=CC=2)C1)C1C=CC=CC=1CCC)(=O)C.[C:56]1([O:62][C:63](Cl)=[O:64])[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>C1(C)C=CC=CC=1>[C:1]([N:4]([CH2:14][CH:15]1[O:20][CH2:19][CH2:18][N:17]([C:63]([O:62][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[O:64])[CH2:16]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][CH3:13])(=[O:3])[CH3:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCCc1ccccc1N(CC1CN(Cc2ccccc2)CCO1)C(C)=O
Agent: Cl
Solvent: Cc1ccccc1
Product: CCCc1ccccc1N(CC1CN(C(=O)Oc2ccccc2)CCO1)C(C)=O

Procedure:
2-(N-Acetyl-2-n-propylanilino)methyl-4-benzylmorpholine (2.2 g.) (prepared by basification of the hydrochloride described above) is azeotroped in toluene (30 ml.) until a clear dry solution is obtained. The solution is cooled and phenylchloroformate (1.2 g.) is added and the mixture is heated under reflux for 18 hours when the toluene is removed under reduced pressure. Crude 2-(N-acetyl-2-n-propylanilino)methyl-4-phenoxycarbonylmorpholine is obtained as an orange coloured oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.[CH3:12]N(C)C=O.N1CCCC1.C(O)(=O)C>CCOCC.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:8]=[CH:12][NH:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(Br)cc1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: [Zn]
Solvent: CCOCC
Solvent: C1CCNC1
Solvent: CC(=O)O
Product: Brc1ccc2cc[nH]c2c1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
Combine 4-bromo-2-nitrotoluene (5.0 g, 23.1 mmol), dimethylformamide (50 ml), DMF-dimethylacetal (9.0 ml, 69.4 mmol), and pyrrolidine (2.0 ml, 23.1 mmol). Heat to 110° C. After 3 hours, cool to room temperature, dilute with ether, and wash with water. Combine the organic layers, and concentrate to give a residue. Combine the residue and 80% aq. acetic acid (120 ml) and heat at 75° C. Add zinc dust (13.1 g, 200.5 mmol) portionwise. Heat to 85° C. After 2 hours, cool and filter. Dilute the filtrate with ether, wash with water dry (Na2SO4), and concentrate to give a residue. Chromatograph the residue eluting with 9:1 hexane:EtOAc to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][O:21][CH3:22])=[C:15]([CH:23]([CH3:25])[CH3:24])[CH:14]=2)=[C:10]([CH3:26])[CH:9]=[C:8]([OH:27])[C:3]=1[C:4](OC)=[O:5].[BH4-].[Na+]>C(O)C.O>[CH3:1][C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][O:21][CH3:22])=[C:15]([CH:23]([CH3:24])[CH3:25])[CH:14]=2)=[C:10]([CH3:26])[CH:9]=[C:8]([OH:27])[C:3]=1[CH2:4][OH:5]
Reactant: COCOc1ccc(Cc2c(C)cc(O)c(C(=O)OC)c2C)cc1C(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COCOc1ccc(Cc2c(C)cc(O)c(CO)c2C)cc1C(C)C
Temperature: 80 °C

Procedure:
To a solution of methyl 2,4-dimethyl-6-hydroxy-3-(4′-methoxymethoxy-3′-iso-propylbenzyl)benzoate in ethanol-water (3.0 mL, 95:5) at room temperature was added NaBH4. The reaction mixture was heated at 80° C. for 4 h and cooled to room temperature. The reaction mixture was quenched with aqueous NH4Cl and extracted with ether. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with 30% acetone in hexanes to afford 2,4-dimethyl-6-hydroxy-3-(4′-methoxymethoxy-3′-iso-propylbenzyl)benzyl alcohol: 1H NMR (300 MHz, CD3OD): δ 6.97 (d, J=2.4 Hz, 1 H), 6.92 (d, J=13.2 Hz, 1 H), 6.68 (dd, J=13.2, 2.4 Hz, 1 H), 6.59 (s, 1 H), 5.17 (s, 2 H), 4.78 (s, 2 H), 3.96 (s, 2H), 3.47 (s, 3 H), 3.30 (m, 1 H), 2.24 (s, 3 H), 2.19 (s, 3 H), 1.18 (d, J=10.8 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=acetone-hexanes (3:7); Rf=0.40.
Reaction SMILES: C1C=CC2N(O)N=[N:7]C=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.CCN(C(C)C)C(C)C.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([C:46]2[CH:51]=[CH:50][C:49]([NH:52][C:53]3[N:58]=[C:57]([CH2:59][CH2:60][C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=4[CH2:67][C:68](O)=[O:69])[C:56]([CH3:71])=[CH:55][N:54]=3)=[CH:48][CH:47]=2)[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].C(=O)([O-])[O-].[NH4+].[NH4+]>C1COCC1.CN(C=O)C>[NH2:7][C:68](=[O:69])[CH2:67][C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][C:61]=1[CH2:60][CH2:59][C:57]1[C:56]([CH3:71])=[CH:55][N:54]=[C:53]([NH:52][C:49]2[CH:48]=[CH:47][C:46]([CH:43]3[CH2:42][CH2:41][N:40]([C:38]([O:37][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:39])[CH2:45][CH2:44]3)=[CH:51][CH:50]=2)[N:58]=1
Reactant: On1nnc2ccccc21
Reactant: Cc1cnc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)nc1CCc1ccccc1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)nc1CCc1ccccc1CC(N)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
HOBt (49 mg, 0.36 mmol), EDCl.HCl (69 mg, 0.36 mmol) and DIPEA (0.21 mL, 1.2 mmol) were added to a stirred solution of 2-(2-(2-(2-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-methylpyrimidin-4-yl)ethyl)phenyl)acetic acid (A55) (127 mg, 0.239 mmol) in dry THF (6 mL) and dry DMF (1 mL) under an atmosphere of nitrogen. After 10 minutes ammonium carbonate (115 mg, 1.20 mmol) was added in one portion and the resulting mixture was stirred at room temperature for 24 hours. The volatiles were removed in vacuo then the residue was partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL). The layers were separated and the aqueous phase was extracted with EtOAc (2×50 mL). The organic extracts were combined, washed with brine and dried over MgSO4. The volatiles were removed under reduced pressure and the residue purified by column chromatography (0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A56 as an off-white solid (66 mg, 52%); 1H NMR (400 MHz, d6-DMSO) δ 9.36 (s, 1H), 8.25-8.16 (m, 1H), 7.74 (d, J=8.7 Hz, 2H), 7.49 (s, 1H), 7.28 (m, 1H), 7.25-7.14 (m, 5H), 7.00 (s, 1H), 4.14 (m, 2H), 3.56 (s, 2H), 3.17-3.04 (m, 2H), 2.98-2.91 (m, 2H), 2.84 (m, 2H), 2.71-2.60 (m, 1H), 2.13 (s, 3H), 1.79 (d, J=11.7 Hz, 2H), 1.59-1.43 (m, 11H). LCMS-A: rt 6.078 min; m/z 530 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])=[N:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=[O:4].ClCCC1C=C[C:38]([C:41](=[O:43])C)=CC=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[C:41]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][N:16]([C@H:25]2[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][C:2]([CH3:1])([CH3:6])[C:3]([OH:5])=[O:4])=[CH:9][N:10]=2)=[CH:20][CH:21]=1)(=[O:43])[CH3:38]
Reactant: CC(=O)c1ccc(CCCl)cc1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Agent: CCOC(=O)CSc1cnc(N)s1
Product: CC(=O)c1ccc(CCN(C(=O)Nc2ncc(SC(C)(C)C(=O)O)s2)[C@H]2CC[C@H](C)CC2)cc1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-phenethyl -ureido]-thiazol-5-ylsulfanyl}-propionic acid using 1-[4-(2-chloro-ethyl)-phenyl]-ethanone and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[CH2:6][NH:7][C:8](=[O:38])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]Br)[CH:30]=2)[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[NH:52]1[CH2:56][CH2:55][C@@H:54]([NH:57][C:58](=[O:60])[CH3:59])[CH2:53]1>CN(C)C=O.O>[C:58]([NH:57][C@H:54]1[CH2:55][CH2:56][N:52]([CH2:35][C:31]2[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=2)[C:28]([NH:27][C:16]2[CH:17]=[CH:18][C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:20][C:15]=2[C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][N:12]=2)[C:8]([NH:7][CH2:6][C:5]2[CH:39]=[CH:40][CH:41]=[C:3]([C:2]([F:43])([F:42])[F:1])[CH:4]=2)=[O:38])=[O:37])[CH2:53]1)(=[O:60])[CH3:59]
Reactant: CC(=O)N[C@@H]1CCNC1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CBr)c2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N[C@H]1CCN(Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)C1
Temperature: 70 °C
Reaction time: 3 h
Yield: 45.8 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-(3-(bromomethyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinamide (100 mg, 0.15 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL), potassium carbonate (62 mg, 0.45 mmol, 2.92 equiv), potassium iodide (5 mg, 0.03 mmol, 0.20 equiv), and (R)—N-(pyrrolidin-3-yl)acetamide (38.5 mg, 0.30 mmol, 1.96 equiv). The resulting solution was stirred for 3 h at 70° C. in an oil bath. The resulting solution was diluted with 150 mL of water. The resulting solution was extracted with 4×100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×200 mL of brine. The mixture was dried over sodium sulfate and concentrated under vacuum. The crude product (100 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 48 mg (30%) of a light yellow solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.925-8.942 (d, J=5.1 Hz, 1H), 8.642-8.672 (d, J=9.0 Hz, 1H), 8.435 (s, 1H), 8.075-8.141 (m, 3H), 7.863-7.880 (m, 1H), 7.537-7.801 (m, 7H), 4.720 (s, 2H), 4.524-4.594 (m, 2H), 4.374-4.418 (m, 1H), 3.628-3.663 (m, 4H), 2.501 (m, 1H), 2.016-2.031 (m, 5H), 1.947 (m, 3H), 1.810-1.826 (m, 2H). MS (ES, m/z): 699 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][CH:13]=[C:14]([C:16]([OH:19])([CH3:18])[CH3:17])[N:15]=3)[S:10][C:3]=12.[CH3:20][N:21]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][C:23]([OH:30])=[N:22]1>>[CH3:20][N:21]1[C:25]([C:26]([F:27])([F:28])[F:29])=[CH:24][C:23]([O:30][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]4[S:12][CH:13]=[C:14]([C:16]([OH:19])([CH3:18])[CH3:17])[N:15]=4)[S:10][C:3]=23)=[N:22]1
Reactant: Cn1nc(O)cc1C(F)(F)F
Reactant: CC(C)(O)c1csc(-c2cc3nccc(Cl)c3s2)n1
Product: Cn1nc(Oc2ccnc3cc(-c4nc(C(C)(C)O)cs4)sc23)cc1C(F)(F)F
Yield: 8 %

Procedure:
The title compound (11 mg, 8%) was prepared from 2-[2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-thiazol-4-yl]-propan-2-ol and 1-methyl-5-trifluoromethyl-1H-pyrazol-3-ol by a procedure analogous to Example 16. C18H15F3N4O2S2: APCI m/z 441.3 (pos.); 1H NMR (CD3OD): δ 8.53 (d, 1H, J=5.6 Hz), 7.91 (s, 1H), 7.48 (s, 1H), 7.07 (d, 1H, J=5.6 Hz), 6.68 (s, 1H), 3.98 (s, 3H), 1.61 (s, 6H) ppm.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[C:6](=[O:20])[CH2:7][NH:8][C:9](=O)[C:10]1[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:12]([OH:14])=[O:13].S(=O)(=O)(O)O>>[F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([C:6]2[O:20][C:9]([C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[C:12]([OH:14])=[O:13])=[N:8][CH:7]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: O=C(CNC(=O)c1ccccc1C(=O)O)c1cccc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccccc1-c1ncc(-c2cccc(C(F)(F)F)c2)o1
Temperature: 0 °C
Yield: 91.1 %

Procedure:
N-(3-trifluoromethylphenacyl) phthalamic acid (9.4 g, 0.027 mol) was added portionwise to conc. sulfuric acid (30 ml) at <10° C. The resultant solution was stirred for 20 hours at room temperature and poured into 600 ml of ice-water to yield 8.2 g of crude 2-[5-(3-trifluoromethylphenyl)-1,3-oxazol-2-yl]benzoic acid as a brown solid; ir (CHCl3) 1720 cm-1. The crude acid was used for subsequent synthesis is obtained.
Reaction SMILES: [CH2:1]([N:8]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH:9]1[CH2:13][CH:12]([C:14]2[N:18]3[C:19]4[CH:25]=[CH:24][N:23](S(C5C=CC(C)=CC=5)(=O)=O)[C:20]=4[N:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]([CH3:36])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1>[CH2:37]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:9]1[CH2:10][CH:11]([CH3:36])[CH:12]([C:14]2[N:18]3[C:19]4[CH:25]=[CH:24][NH:23][C:20]=4[N:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH2:13]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2ncc(C4CC(N(Cc5ccccc5)Cc5ccccc5)CC4C)n23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC1CC(N(Cc2ccccc2)Cc2ccccc2)CC1c1cnc2cnc3[nH]ccc3n12
Temperature: 90 °C
Yield: 55.7 %

Procedure:
N,N-Dibenzyl-3-methyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentan-amine (4.47 g, 7.58 mmol) was dissolved in 1,4-dioxane (40 mL). NaOH (2 N aqueous, 4 mL) was added and the reaction mixture was heated at about 90° C. for about 80 min. The organic solvent was removed under reduced pressure and the residue was treated with saturated aqueous NH4Cl (70 mL) and extracted with DCM (2×60 mL). The combined organic extracts were washed with brine (70 mL), dried over anhydrous MgSO4 and concd under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0-8% MeOH in DCM to yield N,N-dibenzyl-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentan-amine (1.84 g, 56%) as a yellow oil: LC/MS (Table 1, Method a) Rt=2.31 min; MS m/z 436 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])[CH2:3][OH:4].C(N(CC)CC)C.Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.O>C1(C)C=CC=CC=1>[CH3:1][CH:2]1[CH2:3][O:4][C:26](=[O:28])[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:6][CH2:5]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(CO)CCNCc1ccccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC1CCN(Cc2ccccc2[N+](=O)[O-])C(=O)OC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
2-Methyl-4-(2-nitrobenzylamino)butanol (5.00 g, 21.0 mmol), triethylamine (8.49 g, 84.1 mmol) were dissolved in toluene (50 ml). Under ice cooled condition, a solution in which triphosgene (2.50 g, 8.42 mmol) was dissolved in toluene (10 ml) was slowly added dropwise thereto and heated to reflux for six hours after stirred at room temperature for one hour. The reaction mixture was poured into water and, after standing to cool, extracted with ethyl acetate. The organic layer was washed with 0.1 N hydrochloric acid water and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain 6-methyl-3-(2-nitrobenzyl)-[1,3]-oxazepan-2-one (2.00 g).
Reaction SMILES: [Cr:1].[NH:2]([S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11])[S:3]([C:6]([F:9])([F:8])[F:7])(=[O:5])=[O:4]>O>[NH:2]([S:3]([C:6]([F:9])([F:7])[F:8])(=[O:5])=[O:4])[S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11].[NH:2]([S:3]([C:6]([F:9])([F:7])[F:8])(=[O:5])=[O:4])[S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11].[Cr+3:1]
Reactant: [Cr]
Agent: O=S(=O)(NS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: [Cr+3]
Temperature: 150 °C

Procedure:
Chromium metal (1.0 g, 99.95% purity) pieces were suspended in water (20 mL) and hydrogen bis-triflimide (HNTf2) (5 g) was added. This mixture was heated under reflux for 144 hours. The resultant mixture was cooled, filtered and concentrated on a rotary evaporator to give a green solid. The solid were heated at 150° C. at 1 mmHg to remove the residual water and hydrogen bis-triflimide. The solid was thought to contain an oxo chromium bis-triflimide species CrO(NTf2) from the mass of HNTf2 produced in drying process. The unpurified chromium(III) bis-triflimide was found to display catalytic activity in Friedel-Crafts reactions, and was similar in activity to Zn(NTf2)2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([S:18]([O:21]CC(F)(F)F)(=[O:20])=[O:19])=[CH:13]3)=[C:4]([O:27][CH3:28])[CH:3]=1.[OH-].[Na+:30]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([S:18]([O-:21])(=[O:19])=[O:20])=[CH:13]3)=[C:4]([O:27][CH3:28])[CH:3]=1.[Na+:30]
Reactant: COc1cc(Cl)ccc1-c1cccc2cc(S(=O)(=O)OCC(F)(F)F)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1cc(Cl)ccc1-c1cccc2cc(S(=O)(=O)[O-])ccc12
Temperature: 25 °C
Yield: 99.5 %

Procedure:
A round bottomed flask was charged with 2,2,2-trifluoroethyl 5-(4-chloro-2-methoxyphenyl)naphthalene-2-sulfonate (1.729 g, 4.01 mmol) and CH2Cl2 (8.03 mL). Sodium hydroxide (2M in MeOH) (4.01 mL, 8.03 mmol) was added at rt. The solution was capped and maintained at rt for 18 h resulting in a white precipitate. The white solid was collected by vacuum filtration, rinsing with diethyl ether to yield sodium 5-(4-chloro-2-methoxyphenyl)naphthalene-2-sulfonate (1.481 g, 3.99 mmol) as a fluffy white solid. The solid was used directly without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:31][C:13]3[CH:14]=[N:15][C:16]([NH:18][C:19]([C:21]45[CH2:30][CH:25]6[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]6)[CH2:22]4)[CH2:28]5)=[O:20])=[CH:17][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([O-])=O>[Ni].CCO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[NH:31][C:13]3[CH:14]=[N:15][C:16]([NH:18][C:19]([C:21]45[CH2:22][CH:23]6[CH2:29][CH:27]([CH2:26][CH:25]([CH2:24]6)[CH2:30]4)[CH2:28]5)=[O:20])=[CH:17][C:12]=3[N:11]=2)=[CH:8][CH:9]=1
Reactant: O=C(Nc1cc2nc(-c3ccc([N+](=O)[O-])cc3)[nH]c2cn1)C12CC3CC(CC(C3)C1)C2
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc(-c2nc3cc(NC(=O)C45CC6CC(CC(C6)C4)C5)ncc3[nH]2)cc1
Yield: 107.5 %

Procedure:
A solution of 13 (0.200 g, 0.48 mmol) and Raney Nickel (0.200 ml) in EtOH (10 ml) was stirred under H2 atmosphere at 80° C. for 90 min. TLC showed no starting material. The product was freed from catalyst by filtering through a celite pad and evaporated to dryness to afford the amine 14 (0.200 g, 100%) used for the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH:26]=O.[BH4-].[Na+]>C(O)(=O)C>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][CH2:26][C:22]3[O:21][CH:25]=[CH:24][CH:23]=3)[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: O=Cc1ccco1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1CCC(N2C(=O)c3cccc(NCc4ccco4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.4 %

Procedure:
To a suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2 mmol) in acetic acid (20 ml) was added furan-2-carbaldehyde (0.20 g, 2.05 mmol). The mixture was heated to reflux for 5 hours and allowed to cool at room temperature. Sodium borohydride (80 mg, 2 mmol) was added to the reaction mixture. The reaction mixture was stirred for 24 hours. The solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate (100 ml), washed with H2O (3×100 ml), saturated aqueous NaHCO3 (2×100 ml), brine (1×100 ml), and dried. The solvent was evaporated and the residue was purified by chromatography (ethyl acetate/hexane, 1:1) to give 0.25 g (35%) of product as a yellow solid: mp 171-173° C.; 1H NMR (DMSO-d6) δ 11.10 (s, 1H), 7.58 (t, J=7.1 Hz, 2H), 7.18 (d, J=8.6 Hz, 1H), 7.08-6.97 (m, 2H), 6.39-6.36 (m, 2H), 5.06 (dd, J=5.2 and 12.4 Hz, 1H), 4.57 (d, J=6.0 Hz, 2H), 2.96-2.82 (m, 1H), 2.63-2.46 (m, 2H), 2.06-2.02 (m, 1H; 13C NMR (DMSO-d6) δ 172.76, 170.01, 168.75, 167.21, 151.97, 145.81, 142.42, 136.05, 132.09, 117.60, 111.04, 110.42, 109.73, 107.38, 48.57, 30.95, 22.10; Anal. Calcd. For C11H15N3O, C, 61.19; H, 4.28; N, 11.89. Found: C, 61.02; H, 4.24; N, 11.81.
Reaction SMILES: [C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[C:16]#[N:17])([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]I)#[N:2].C(N(CC)CC)C.[C:25]([C:27]1[CH:28]=[C:29]([CH:39]=[CH:40][CH:41]=1)[O:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)#[N:26]>C(#N)C>[C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[C:16]#[N:17])([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][N:36]1[CH2:35][CH2:34][N:33]([CH2:32][CH2:31][O:30][C:29]2[CH:39]=[CH:40][CH:41]=[C:27]([C:25]#[N:26])[CH:28]=2)[CH2:38][CH2:37]1)#[N:2]
Reactant: CC(C)C(C#N)(CCCI)c1sccc1C#N
Reactant: N#Cc1cccc(OCCN2CCNCC2)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)C(C#N)(CCCN1CCN(CCOc2cccc(C#N)c2)CC1)c1sccc1C#N
Reaction time: 72 h

Procedure:
In 1.5 ml of acetonitrile was dissolved 111 mg (0.31 mmol) of 4-cyano-5-methyl-4-(3-cyano-2-thienyl)hexyl iodide. To the mixture were added 56.2 μl (0.40 mmol) of triethylamine and 109 mg (0.47 mmol) of 1-(3-cyanophenoxyethyl)piperazine, followed by stirring for 3 days. The organic layer separated by adding ethyl acetate and brine to the reaction solution was dried over magnesium sulfate, and then evaporated, to give a crude product. The crude product was subjected to 12.5 g of Cromatorex NH silica gel (ethyl acetate/hexane-1/2), to give 144 mg (quantitative) of the title compound as a yellow syrup.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:27]([C:30]3[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:45]2[CH:46]=[C:47]([NH:51][S:52]([CH3:55])(=[O:54])=[O:53])[CH:48]=[CH:49][CH:50]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.C(O)C.O>[S:27]([N:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:45]3[CH:46]=[C:47]([NH:51][S:52]([CH3:55])(=[O:53])=[O:54])[CH:48]=[CH:49][CH:50]=3)[CH:3]=[C:4]2[C:10]([C:11]2[CH:12]=[N:13][N:14]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[CH:15]=2)=[CH:9]1)([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)c3cc(Br)cnc32)cc1
Reactant: CC1(C)OB(c2cccc(NS(C)(=O)=O)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)c3cc(-c4cccc(NS(C)(=O)=O)c4)cnc32)cc1
Yield: 100.9 %

Procedure:
Using similar reaction conditions as described in step 2 of example 1, 5-bromo-1-tosyl-3-(1-(3-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine (165 mg, 0.28 mmol) was coupled with N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) methane sulfonamide (Intermediate 3) (119 mg, 0.401 mmol) in sodium carbonate (91 mg, 0.86 mmol), bis(triphenyl phosphine)palladium(ii) dichloride (10 mg, 0.014 mmol) and toluene/ethanol/water (15/6/2 ml) to afford 188 mg (98.4% yield) of the pure product after column purification using 60% ethyl acetate in hexane as eluent. MS: m/z=666.10 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O[CH:22](OCC)[N:23]([CH3:25])[CH3:24])C>C1(C)C=CC=CC=1>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:22][N:23]([CH3:25])[CH3:24])[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: CCOC(OCC)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)C=Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reaction time: 5 h

Procedure:
With the exclusion of moisture, 200 mg (0.767 mmol) of 3-amino-4-(3-chlorophenylamino)-1 H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) are suspended in 3.2 ml of toluene; 150 μl (0.87 mmol) of N,N-dimethylformamide diethyl acetal in 6 ml of toluene are added and the reaction mixture is heated to boiling. After 5 hours, filtration is carried out, followed by thorough washing with toluene. 4-(3-Chloro-phenylamino)-3-(dimethylaminomethyleneamino)-1H-pyrazolo[3,4-d]pyrimidine is obtained; m.p. 243-245° C.; HPLC: tRet(grad20-100/20)=9.7; FAB-MS: (M+H)+=316.