Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:9]2[C:5]([S:6][C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:11]=3)=[N:8]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([C:35]([F:38])([F:37])[F:36])[C:31]([NH2:34])=[N:32][CH:33]=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.O1CCOCC1>[CH3:19][S:16]([C:12]1[CH:11]=[C:10]([C:7]2[S:6][C:5]3=[N:4][CH:3]=[C:2]([C:28]4[CH:29]=[C:30]([C:35]([F:38])([F:37])[F:36])[C:31]([NH2:34])=[N:32][CH:33]=4)[N:9]3[N:8]=2)[CH:15]=[CH:14][CH:13]=1)(=[O:18])=[O:17]
Reactant: CC1(C)OB(c2cnc(N)c(C(F)(F)F)c2)OC1(C)C
Reactant: CS(=O)(=O)c1cccc(-c2nn3c(I)cnc3s2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cccc(-c2nn3c(-c4cnc(N)c(C(F)(F)F)c4)cnc3s2)c1
Temperature: 110 °C
Yield: 20.2 %

Procedure:
A mixture of 5-Iodo-2-(3-methanesulfonyl-phenyl)-imidazo[2,1-b][1,3,4]thiadiazole (0.091 g, 0.225 mmol, 1 eq), and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridin-2-ylamine (0.097 g, 0.337 mmol, 1.5 eq), PdCl2(PPh3)2 (32 mg, 0.045 mmol, 0.2 eq) and 2M Na2CO3 (1 mL) and dioxane (5 mL). The reaction mixture was heated at 110° C. for 24 h. The solvent was evaporated, the residue was redissolved in DCM/water (150 mL) and extacted with DCM (2×80 mL). The organic layer was dried (MgSO4), filtered and evaporated. The residue was triturated from MeOH and filtered off. The solid was purified by column chromatography (0-5% MeOH in DCM) to give the desired product (20 mg, 20%) as a yellow solid. HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=5.25 min, [M+H]+ m/z 440.0; 1H NMR (300 MHz, DMSO) δ 8.90 (d, J=1.8 Hz, 1H), 8.44 (d, J=1.6 Hz, 1H), 8.37 (d, J=2.0 Hz, 1H), 8.33 (d, J=7.9 Hz, 1H), 8.19 (d, J=8.1 Hz, 1H), 7.92 (t, J=7.9 Hz, 1H), 7.84 (s, 1H), 6.74 (s, 2H), 3.32 (s, 3H).
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].N1C=CC=CC=1.Cl[C:17]([C:19]1[C:31]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[C:32]([C:35]#[N:36])[C:33]#[N:34])[C:23]=2[CH:22]=[CH:21][CH:20]=1)=[O:18]>ClCCl>[C:35]([C:32]([C:33]#[N:34])=[C:24]1[C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([C:17]([O:2][C:1]3[CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=3)=[O:18])[C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)#[N:36]
Reactant: N#CC(C#N)=C1c2ccccc2-c2c(C(=O)Cl)cccc21
Reactant: Oc1cc(O)cc(O)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#CC(C#N)=C1c2ccccc2-c2c(C(=O)Oc3cc(O)cc(O)c3)cccc21
Yield: 58.3 %

Procedure:
A solution of 30.0 grams of phloroglucinol and 70 milliliters of pyridine in 300 milliliters of dichloromethane was stirred at room temperature under a nitrogen atmosphere. A solution of 8.0 grams of (4-chloroformyl-9-fluorenylidene)malononitrile in 400 milliliters of dichloromethane was added over a period of 1 hour. After addition, the reaction mixture was further stirred for another hour. The mixture was washed three times with dilute aqueous HCl solution, twice with dilute aqueous NaHCO3 solution, and once with water. The solution was dried, filtered and evaporated under reduced pressure to give the crude product. Recrystallization from methanol afforded 6.1 grams of (1b), mp., 255.5°-257° C.
Reaction SMILES: [CH3:1][C@@H:2]1[C@@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:3]1.C(N(C)C(C)C)(C)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:1][C@@H:2]1[C@@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:3]1[S:20]([CH3:19])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1N[C@@H]1c1ccccc1
Agent: CC(C)N(C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1[C@@H](c2ccccc2)N1S(C)(=O)=O
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To (2R,3R)-2-Methyl-3-phenylaziridine (38b, 0.08 g, 0.60 mmol) in CH2Cl2 (3 ml) was is added N,N-Diisopropylmethyamine (0.219 ml, 1.32 mmol) and the reaction mixture was cooled to −10° C. before methansulfonyl chloride (0.051 ml, 0.66 mmol) was added The mixture was stirred for 30 min at −10° C. than at room temperature for 1 h. The crude sample was added to a Chromasil C18 column and was eluted with MeCN/H2O 35-70%, 20 min.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1.C1([O:31][C:32](=O)[NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[N:35]=2)C=CC=CC=1.C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:32]([NH:33][C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:41])[F:43])[N:35]=4)=[O:31])=[CH:22][CH:23]=3)[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CCCCOC(=O)c1cc(-c2ccc(N)cc2)c2c(N)ncnn12
Reactant: O=C(Nc1cccc(C(F)(F)F)n1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCOC(=O)c1cc(-c2ccc(NC(=O)Nc3cccc(C(F)(F)F)n3)cc2)c2c(N)ncnn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
To a solution of butyl 4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxylate (118.0 mg, 0.36 mmol) in DMF (3.5 mL) was added phenyl[6-(trifluoromethyl)pyridin-2-yl]carbamate (153.5 mg, 0.54 mmol), followed by triethylamine (0.10 mL, 0.73 mmol). The solution was stirred at rt overnight and then purified directly by HPLC using a gradient of 50-80% MeCN in water to yield 107.7 mg (58%) of the title compound as a white solid. 1H-NMR (DMSO-d6) δ 9.88 (s, 1 H), 9.73 (s, 1 H), 8.08 (s, 1 H), 8.04 to 7.97 (m, 2 H), 7.58 (d, J=8.6 Hz, 2 H), 7.51 to 7.49 (m, 1 H), 7.44 (d, J=8.5 Hz, 2 H), 7.22 (s, 1 H), 4.26 (t, J=6.6 Hz, 2 H), 1.71-1.64 (m, 2 H), 1.47-1.38 (m, 2 H), 0.93 (t, J=7.3, 3 H); MS [M+H]+=514.2; LCMS RT=3.49 min.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][O:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH3:25].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[O:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH2:23][CH2:24][CH3:25]
Reactant: CCCC=O
Reactant: O=C1COC(=O)N1CCCCCc1cccc2nccn12
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCC=C1OC(=O)N(CCCCCc2cccc3nccn23)C1=O

Procedure:
To a solution of 3.45 g (12 mmol) of 3-[5-(imidazo[1,2-a]pyridin-5-yl)pentyl]oxazolidine-2,4-dione and 1.08 ml (12 mmol) of n-butyraldehyde in 50 ml of ethanol, 0.12 ml (1.2 mmol) of piperidine was added, followed by refluxing for 16 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, hexane/ethyl acetate=1/2→ethyl acetate/ethanol=10/1) to yield 1.36 g (33.2%, light yellow oily substance) of the desired product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([O:38]C2C=CC=CC=2)=O)=[C:31]([F:45])[CH:30]=1)#[N:2].[CH:46]1([NH2:49])[CH2:48][CH2:47]1>O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:49][CH:46]2[CH2:48][CH2:47]2)=[O:38])=[C:31]([F:45])[CH:30]=1)#[N:2]
Reactant: NC1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cc3nccc(Oc4ccc(NC(=O)Oc5ccccc5)c(F)c4)c3cc2C#N)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2cc3nccc(Oc4ccc(NC(=O)NC5CC5)c(F)c4)c3cc2C#N)CC1

Procedure:
tert-Butyl 4-(((6-cyano-4-(3-fluoro-4-((phenoxycarbonyl)amino)phenoxy)-7-quinolyl)oxy)methyl)-1-piperidinecarboxylate (490 mg), cyclopropylamine (0.72 ml) and tetrahydrofuran (5 ml) were stirred together at 60° C. for 35 minutes. Silica gel was added to the reaction solution and the solvent was distilled off under reduced pressure for adsorption. The reaction solution-adsorbed silica gel was purified by column chromatography (ethyl acetate, followed by ethyl acetate:methanol=20:1) in a dry column packed with silica gel, to obtain 340 mg of a light yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)=[O:4].[N+:18]([C:21]1[CH:51]=[CH:50][C:24]([CH2:25][O:26][C:27]([N:29]=[C:30]([NH:36][C:37](=[O:49])[O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=2)N2C=CC=N2)=[O:28])=[CH:23][CH:22]=1)([O-:20])=[O:19].C(OCC)(=O)C>O1CCCC1>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([CH2:25][O:26][C:27]([N:29]=[C:30]([NH:36][C:37]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=2)=[O:49])[NH:1][CH2:2][C:3]([NH:5][C@H:6]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]2)=[O:4])=[O:28])=[CH:50][CH:51]=1)([O-:20])=[O:19]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)CN)C1
Reactant: O=C(N=C(NC(=O)OCc1ccc([N+](=O)[O-])cc1)n1cccn1)OCc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)CNC(=NC(=O)OCc2ccc([N+](=O)[O-])cc2)NC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (3S)-3-(2-aminoacetylamino)-1-pyrrolidinecarboxylate (3.07 g) in anhydrous tetrahydrofuran (45 ml), a solution of 4-nitrobenzyl [(4-nitrobenzyloxy)carbonylimino-pyrazol-1-ylmethyl]carbamate (5.38 g) in tetrahydrofuran (35 ml) was added under ice cooling, followed by stirring at room temperature for 30 minutes. Ethyl acetate was added to the reaction mixture. The resulting mixture was washed with water, an aqueous solution of potassium hydrogensulfate and saturated saline, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by chromatography through a silica gel column (ethyl acetate-dichloromethane), whereby the title compound (7.82 g) was obtained as an amorphous substance.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C(N(CC)CC)C.C[C@:18]1([OH:24])[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:20]2[CH2:21][CH2:22][CH2:23][C@H:18]([OH:24])[CH2:19]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: C[C@]1(O)CCCNC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O[C@H]1CCCN(Cc2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
A mixture of 4-bromobenzyl bromide (1.0 g, 4.0 mmol), triethylamine (0.84 mL, 6.0 mmol) and (S)-3-methyl-piperidin-3-ol (1.11 g, 8.0 mmol) in THF (20 mL) was stirred at ambient temperature for 16 h. The solvent was evaporated and the resultant residue diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered and evaporated. The resultant residue was purified by flash chromatography (silica, Biotage 50 g column, 50-100% ethyl acetate in cyclohexane) to afford the title compound (0.8 g, 74%). 1H NMR (CDCl3, 300 MHz): 7.46-7.40 (m, 2H), 7.21-7.14 (m, 2H), 3.85-3.76 (m, 1H), 3.45 (s, 2H), 2.45 (s, 3H), 2.29-2.16 (m, 1H), 1.86-1.70 (m, 1H), 1.67-1.45 (m, 3H) plus 1 exchangeable not observed. LCMS (Method G): RT=1.42 min, M+H+=270.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[H-].[Na+].[CH3:9][Si:10]([CH2:13][CH2:14][O:15][CH2:16]Cl)([CH3:12])[CH3:11]>O1CCCC1>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([CH2:16][O:15][CH2:14][CH2:13][Si:10]([CH3:12])([CH3:11])[CH3:9])[CH:6]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cn(COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.8 %

Procedure:
Into a 1-L three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-methyl-1H-imidazole (10 g, 121.8 mmol) in tetrahydrofuran (200 mL). This was followed by the addition of sodium hydride (7.32 g, 182.7 mmol, 60%) in several batches at 0° C. and stirred for 1 h at room temperature. To this was added SEM-Cl (30.5 g, 199.7 mmol) at 0° C. The mixture was stirred for 1 h at room temperature, then carefully quenched with 50 mL of brine. The aqueous phase was extracted with 1×800 mL of ethyl acetate. The organic layer was washed with 1×300 mL of brine, 2×300 mL of sodium bicarbonate (sat.), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:1) ethyl acetate as eluent to furnish 9 g (35%) of the title compound as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[C:34]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)(=[O:37])[NH:35][NH2:36]>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:36][NH:35][C:34]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:37])=[O:16])=[CH:17][CH:18]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)NNC(=O)OCc2ccccc2)cc1
Reaction time: 0.17 h
Yield: 45.3 %

Procedure:
A solution containing 4-t-butoxycarbonylaminomethylbenzoic acid (5.0 g) and triethylamine (3.0 ml) in dry THF (180 ml) was treated at 10° C. with isobutyl chloroformate (2.7 ml) and the resulting mixture was stirred for 10 minutes. A solution of benzyl carbazate (3.4 g) in THF (20 ml) was added and the mixture was stirred for 15 hours at ambient temperature. The resulting precipitate was removed by filtration and the filtrate was diluted with ethyl acetate (500 ml) and washed with water (3×100 ml) and with saturated brine (100 ml). The organic solution was dried (MgSO4) and evaporated to a volume of 150 ml. After 1 hour the mixture was filtered to give benzyl 3-(4-t-butoxycarbonylaminomethylbenzoyl)carbazate (3.6 g) as colourless prisms; m.p. 160°-162° C.; NMR Spectrum 1.4 (9H, s); 4.2 (2H, d); 5.1 (2H, s); 7.2-7.5 (2H+5H, m); 7.8 (2H, d); 9.3 (1H, s); 10.3 (1H, s).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[CH3:16][N:17]([CH3:19])[CH:18]=[CH:10][C:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:13])[F:1])=[CH:8][CH:7]=1)=[O:11]
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: COC(OC)N(C)C
Product: CN(C)C=CC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.9 %

Procedure:
A solution of 1-[4-(trifluoromethyl)phenyl]ethanone (2 g, 10.63 mmol, Sigma-Aldrich) in dimethylformamide-dimethylacetal (5 ml, 37.3 mmol) was heated to 110° C. and stirred for 18 hours. The reaction mixture was cooled to room temperature then diluted with iso-hexanes (20 ml). The resulting precipitate was filtered then washed with a minimum of iso-hexane to yield the title compound as a yellow solid (1.29 g)
Reaction SMILES: S(Cl)([Cl:3])=O.[S:5]([CH:9]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)[C:10](O)=[O:11])([OH:8])(=[O:7])=[O:6]>CN(C)C=O.CCOCC>[S:5]([CH:9]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)[C:10]([Cl:3])=[O:11])([OH:8])(=[O:7])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C(c1ccc([N+](=O)[O-])cc1)S(=O)(=O)O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(Cl)C(c1ccc([N+](=O)[O-])cc1)S(=O)(=O)O
Yield: 81.3 %

Procedure:
6.58 Grams (5.7 × 10-2M) of thionyl chloride, 2 ml. of ether and 2 drops of dimethylformamide were added to 1.5 g. (5.7 × 10-3M) of α-sulfo-α-(p-nitrophenyl)acetic acid to allow to react for 14.5 hours at room temperature. The reaction product was subjected to the evaporation to dryness under reduced pressure to obtain a crude desired product. Yield 81.3%.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[N:10]=[CH:9][NH:8][N:7]=1)(=[O:5])=[O:4])[CH3:2].[CH2:11]([N:14]([CH2:18][CH:19]=[CH2:20])[C:15](Cl)=[O:16])[CH:12]=[CH2:13].O1CCCC1>C(N(CC)CC)C>[CH2:11]([N:14]([CH2:18][CH:19]=[CH2:20])[C:15]([N:8]1[CH:9]=[N:10][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[N:7]1)=[O:16])[CH:12]=[CH2:13]
Reactant: CCS(=O)(=O)c1nc[nH]n1
Reactant: C=CCN(CC=C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCN(CC=C)C(=O)n1cnc(S(=O)(=O)CC)n1

Procedure:
A mixture of 6.45 g. 3-ethylsulphonyl-1,2,4-triazole, 6.6 g. diallylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 8 ml. dry triethylamine was refluxed under anhydrous conditions for 1.5 hours. The cooled reaction mixture was filtered and the filtrate distilled under reduced pressure to remove solvent and give a product which distilled at 187° C./0.2 mm. This product solidified and was recrystallized from petroleum ether (b.p. 60° - 80° C.) to give 1-diallylcarbamoyl-3-ethylsulphonyl-1,2,4-triazole, m.p. 39° - 42° C. Elemental analysis satisfactory.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[NH2:9][C:10]1[C:19]2[N:20]=[C:21]([CH2:28][CH2:29][CH2:30][CH3:31])[N:22]([CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])[C:18]=2[C:17]2[N:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1>>[NH2:9][C:10]1[C:19]2[N:20]=[C:21]([CH2:28][CH2:29][CH2:30][CH3:31])[N:22]([CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[C:18]=2[C:17]2[N:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Reactant: O=C(Cl)c1ccco1
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)c1ccco1
Yield: 29.2 %

Procedure:
Using the general method of Example 47, furoyl chloride (15.8 μL, 0.16 mmol) was reacted with 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.05 g, 0.16 mmole) to provide 0.019 g of N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-2-furamide as a white solid. 1H NMR (300 MHz, CDCl3) δ8.58 (dd, J=4.4, 1.5 Hz, 1H), 8.06 (dd, J=8.6, 1.6 Hz, 1H), 7.41 (dd, J=8.5, 4.4 Hz, 1H), 7.33 (m, 1H), 7.08 (dd, J=3.5, 0.6 Hz, 1H), 6.84 (m, 1H), 6.47 (dd, J=3.5, 1.7 Hz, 1H), 4.86 (apparent t, J=7.7 Hz, 2H), 3.59 (apparent q, J=6.5 Hz, 2H), 2.92 (apparent t, J=7.8 Hz, 2H), 1.7-2.1(m, 6H), 1.51 (m, 2H); 1.00 (t, J=7.3 Hz, 3H); HRMS (EI) calcd for C22H26N6O2 (M+) 406.2117, found 406.2121.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][C:20]=1[C:21](O)=[O:22]>>[Cl:18][C:19]1[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][C:20]=1[C:21]([NH:15][CH2:14][C:13]([C:11]1[N:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[O:9][CH:10]=1)([CH3:17])[CH3:16])=[O:22]
Reactant: CC(C)(CN)c1coc(-c2ccc(F)cc2)n1
Reactant: N#Cc1ccc(Cl)c(C(=O)O)c1
Product: CC(C)(CNC(=O)c1cc(C#N)ccc1Cl)c1coc(-c2ccc(F)cc2)n1
Yield: 44 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and 2-chloro-5-cyanobenzoic acid as described in example 8 step 6 (300 mg, yield 44%). 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J=2.0 Hz, 1H), 7.98-7.95 (m, 2H), 7.66-7.63 (m, 1H), 7.56-7.54 (d, J=8.3 Hz, 1H), 7.48 (s, 1H), 7.39 (m, 1H), 7.17-7.13 (t, J=8.8 Hz, 2H), 3.68-3.66 (d, J=5.8 Hz, 2H), 1.41 (s, 6H). MS (ESI) m/z: Calculated for C21H17ClFN3O2: 397.10. found: 396.4 (M−H)−.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[Cl:33])[C:27](Cl)=[O:28].CCN(C(C)C)C(C)C>C1COCC1>[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[Cl:33])[C:27]([NH:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22])=[O:28]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3ccc(CNC(=O)c4ccc(Cl)c(Cl)c4)cc3C2=O)C(=O)N1
Temperature: 40 °C
Yield: 89.1 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and 3,4-dichlorobenzoyl chloride (0.69 g, 3.30 mmol) in THF (20 mL), was added DIPEA (1.05 mL, 6.00 mmol) at room temperature under nitrogen. The mixture was heated to 40° C. for 18 h then cooled to rt. The solvent was removed in vacuo and the residue was dissolved in EtOAc (100 mL). The organic layer was washed with dil. aq. HCl (2×150 mL), sat. NaHCO3 (2×150 mL), water (100 mL), dried (MgSO4) and then concentrated. The product was dried in vacuo to give 3,4-dichloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-benzamide as a white solid (1.23 g, 89% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 9.40 min (98.44%); mp: 253-255° C.; 1H NMR (DMSO-d6) δ 2.03-2.07 (m, 1H, CHH), 2.43-2.62 (m, 2H, CHH, CHH), 2.81-2.96 (m, 1H, CHH), 4.65 (d, J=5.7 Hz, 2H, CH2), 5.15 (dd, J=5.2, 12.5 Hz, 1H, CH), 7.77-7.92 (m, 5H, Ar), 8.14 (d, J=1.8 Hz, 1H, Ar), 9.40 (t, J=5.7 Hz, 1H, NH), 11.13 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.93, 42.77, 49.01, 122.14, 123.57, 127.62, 129.27, 129.90, 130.81, 131.36, 131.62, 133.55, 134.23, 134.29, 147.07; Anal Calcd for C21H15N3O5Cl2: C, 54.80; H, 3.28; N, 9.13. Found: C, 54.76; H, 3.29; N, 8.87.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[CH3:29])[CH2:5][N:6]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:16][CH2:15][C@@H:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[C@H:13](O)[CH2:12]2)[C:7]1=[O:25].CCN(S(F)(F)[F:36])CC>C(Cl)Cl>[F:36][C@H:13]1[C@H:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH2:15][CH2:16][N:11]([CH:8]2[CH2:9][CH2:10][N:6]([CH2:5][C:4]3[CH:26]=[CH:27][C:28]([CH3:29])=[C:2]([F:1])[CH:3]=3)[C:7]2=[O:25])[CH2:12]1
Reactant: CCN(CC)S(F)(F)F
Reactant: Cc1ccc(CN2CCC(N3CC[C@@H](c4ccc(O)cc4)[C@H](O)C3)C2=O)cc1F
Solvent: ClCCl
Product: Cc1ccc(CN2CCC(N3CC[C@@H](c4ccc(O)cc4)[C@H](F)C3)C2=O)cc1F
Reaction time: 1 h
Yield: 7.8 %

Procedure:
To a solution of (±)-rel-1-(3-fluoro-4-methylbenzyl)-3-((3S,4S)-3-hydroxy-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one (280 mg, 0.7 mmol) in DCM (20 mL) was added DAST (0.5 mL, 3.5 mmol) and the reaction mixture was stirred under nitrogen for 1 h. The reaction was then quenched by the addition of 100 mL of a saturated sodium bicarbonate solution and the mixture was diluted with 100 mL of ethyl acetate. The organic layer was separated, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was subjected to preparative HPLC (method B) to yield 22 mg of (±)-rel-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one as a mixture of 4 diastereomers. LCMS (method P) RT 1.64 min; m/z=401.0 (M+H+).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15](I)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([O:24][C:25]([N:27]1[CH2:30][CH:29](I)[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]([N:27]1[CH2:30][CH:29]([C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[N:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:11]=[CH:12]3)[CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(I)ccc21
Product: CC(C)(C)OC(=O)N1CC(c2ccc3c(ccn3S(=O)(=O)c3ccccc3)c2)C1

Procedure:
This compound was prepared from 1-benzenesulfonyl-5-iodo-1H-indole and 3-iodoazetidin-1-carboxylic acid tert-butyl ester by the method outlined under 1.b). ESI-MS [m/z]: 357.05 [M-(C4H9)+H]+.