Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([CH2:41][OH:42])[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl.[CH3:44][N:45]([CH3:52])[CH2:46][CH2:47][CH2:48][C:49](O)=[O:50].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:44][N:45]([CH3:52])[CH2:46][CH2:47][CH2:48][C:49]([O:42][CH2:41][CH:21]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:20][O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:50]
Reactant: CN(C)CCCC(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCCOCC(CO)OCCCCCCCC/C=C\CCCCCCCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCCOCC(COC(=O)CCCN(C)C)OCCCCCCCC/C=C\CCCCCCCC
Reaction time: 8 h
Yield: 87.1 %

Procedure:
In 6 ml of methylene chloride-N,N-dimethylformamide (1:2) was dissolved 120 mg (0.20 mmol) of 1,2-O-dioleylglycerol, followed by addition of 168 mg (1 mmol) of 4-dimethylaminobutyric acid hydrochloride. Then, 206 mg (1 mmol) of N,N'-dicyclohexylcarbodiimide (DCC) and 25 mg (0.2 mmol) of 4-dimethylaminopyridine were further added and the reaction was conducted at ambient temperature overnight. The precipitated byproduct urea was filtered off using a glass filter and the filtrate was concentrated to dryness under reduced pressure and treated with methylene chloride-saturated aqueous sodium hydrogen carbonate solution. After phase separation, the methylene chloride layer was dried over sodium sulfate and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography (silica gel/methylene chloride-methanol) to provide 123 mg (87%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH2:7]2.BrC1C=CC=C(Br)C=1O.[CH3:21][N:22](C)C=O>C(OCC)C.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[C:21]#[N:22])[CH2:7][CH2:8][CH2:9]1
Reactant: CN(C)C=O
Reactant: Brc1cccc2c1OCCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Oc1c(Br)cccc1Br
Agent: [C-]#N
Solvent: CCOCC
Product: N#Cc1cccc2c1OCCC2
Temperature: 90 °C
Yield: 35 %

Procedure:
To a solution of 8-bromo-chroman (1.434 g, 6.730 mmol, prepared from 2,6-dibromo-phenol using the procedure reported by Thomas, G. H. et al. Tetrahedron Lett. 1998, 39, 2219-22) in dimethylformamide (10 mL) at room temperature was added zinc cyanide (790 mg, 6.730 mmol). The mixture was degassed by passing argon through for 2 h before tetrakis(triphenylphosphine)palladium (778 mg, 0.673 mmol) was added. The reaction mixture was heated at 90° C. for 12 h. Upon cooling to room temperature, it was diluted with diethyl ether (100 mL) and washed with sodium bicarbonate, brine and dried over anhydrous sodium sulfate. The solid was filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 10-20% ethyl acetate in hexanes yielded chroman-8-carbonitrile (370 mg, 35%).
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH2:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1.C(C=P(CCCC)(CCCC)CCCC)#N.[CH2:41]([N:48]1[CH2:53][CH2:52][CH:51](O)[CH2:50][CH2:49]1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CO>[CH2:41]([N:48]1[CH2:53][CH2:52][CH:51]([CH:18]([S:15]([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)[CH2:50][CH2:49]1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: O=S(=O)(Cc1ccncc1)c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CO
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1ccncc1)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 34.8 %

Procedure:
A toluene (5 ml) solution of the 4-(4-chlorophenylsulfonylmethyl)pyridine (70 mg, 0.261 mmol) obtained in Referential Example 2,1-benzylpiperidin-4-ol (103 mg, 0.538 mmol) and cyanomethylenetri-n-butylphosphorane (129 mg, 0.538 mol) was heated under reflux for 3 days under an argon atmosphere. After cooling to room temperature, 1-benzylpiperidin-4-ol (103 mg, 0.538 mmol) and cyanomethylenetri-n-butylphosphorane (129 mg, 0.538 mol) were added to the reaction mixture. Under an argon atmosphere, the resulting mixture was heated under reflux for 22 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the methanol:methylene chloride (=1:10) eluate was concentrated under reduced pressure. The residue thus obtained was purified by high performance liquid chromatography (by using a mixed solvent system of water/acetonitrile/formic acid) to give the title compound (40 mg, 35%) as an amorphous substance.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH2:8]([O:10][C:11]1[C:16](C)=[CH:15][N+:14]([O-])=[C:13](C)[C:12]=1[CH3:20])[CH3:9]>C(Cl)(Cl)Cl>[C:5]([O:4][CH2:1][C:2]1[C:16]([CH3:15])=[C:11]([O:10][CH2:8][CH3:9])[C:12]([CH3:20])=[CH:13][N:14]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CCOc1c(C)c[n+]([O-])c(C)c1C
Solvent: ClC(Cl)Cl
Product: CCOc1c(C)cnc(COC(C)=O)c1C

Procedure:
75 ml of acetic anhydride were added dropwise at room temperature to a solution of 31,3 g of 4-ethoxy-2,3,5-trimethylpyridine 1-oxide in 100 ml of chloroform. After boiling under reflux for 16 hours the solution was evaporated, the residue was dissolved in 100 ml of toluene and again evaporated. The residue was taken up in 250 ml of ethyl acetate, whereupon it was extracted three times with 100 ml of saturated sodium bicarbonate solution. The organic phase was dried over sodium sulfate and evaporated in vacuo. The product was chromatographed on 170 g of silica gel with ether. There was obtained (4-ethoxy-3,5-dimethyl-2-pyridyl)methyl acetate in the form of an oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:6][C:7]1[C:15](O)=[C:14]([O:17][CH3:18])[CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH3:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N(C)C)=O)=NC(N(C)C)=O>C1COCC1>[CH3:18][O:17][C:14]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[C:7]2[CH2:6][N:4]([CH3:5])[CH2:3][CH2:2][O:1][C:15]=12
Reactant: COc1cc2c(ccn2S(=O)(=O)c2ccccc2)c(CN(C)CCO)c1O
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc2c(ccn2S(=O)(=O)c2ccccc2)c2c1OCCN(C)C2
Temperature: 150 °C
Yield: 36.1 %

Procedure:
THF (15 mL) was added to a pyrex tube charged with 4-{[(2-hydroxyethyl)(methyl)amino]methyl}-6-methoxy-1-(phenylsulfonyl)-1H-indol-5-ol (Intermediate 16, 1.02 mmol, 400 mg), triphenylphosphine (2.05 mmol, 537 mg) and 1,1′-azobis(N,N-dimethylformamide) (2.05 mmol, 353 mg). The reaction mixture was heated at 150° C. for 90 minutes in a microwave heater. The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound (137 mg). MS m/z 373 [M+H]+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:21])=[C:9]2[C:13](=[CH:14][CH:15]=1)[C@@H:12]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:11][CH2:10]2)(=O)=O.[CH3:24][N:25]1C(=O)CCC1>[C-]#N.[Zn+2].[C-]#N.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].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[C:24]([C:7]1[C:8]([CH3:21])=[C:9]2[C:13](=[CH:14][CH:15]=1)[C@@H:12]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:11][CH2:10]2)#[N:25]
Reactant: CN1CCCC1=O
Reactant: COC(=O)C[C@H]1CCc2c1ccc(OS(=O)(=O)C(F)(F)F)c2C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COC(=O)C[C@H]1CCc2c1ccc(C#N)c2C
Reaction time: 16 h

Procedure:
To a solution of methyl (R)-(5-Trifluoromethylsulfonyloxy-4-methyl-indan-1-yl)acetate (1.00 g, 2.84 mmol, from Step I) in N-methyl pyrrolidinone (13 mL) under argon, zinc cyanide (267 mg, 2.27 mmol), Pd2dba3 (13.0 mg, 14.2 μmol) and dppf (19.0 mg, 34.1 μmol) and the reaction mixture was heated to 100° C. After 16 hr, the reaction mixture was concentrated in vacuo and partitioned between EtOAc and H2O. The layers were separated and the organic layer was washed with H2O, brine and dried over MgSO4. The mixture was filtered, the filtrate concentrated in vacuo, and the residue purified by flash chromatography (5, 10% EtOAc/hexanes) on SiO2 to give 553 mg of the title compound as a white solid: 1H NMR (500 MHz, CDCl3) δ 1.76-1.80 (m, 1H), 2.41-2.50 (m, 5H), 2.73 (dd, 1H, J=5.8, 15.8 Hz), 2.78-2.84 (m, 1H), 2.91 (ddd, 1H, J=4.8, 8.7, 13.5 Hz) 3.61-3.67 (m, 1H), 3.71, (s, 3H), 7.07 (d, 1H, J=7.8 Hz), 7.43 (d, 1H, J=7.7 Hz).
Reaction SMILES: CO[CH2:3][C:4]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]2[C:7]([C@H:8]3[CH2:18][C@H:9]3[CH2:10][O:11]2)=[CH:6][CH:5]=1.C([Cl:22])(=O)C>C(OCC)C.[Cl-].[Zn+2].[Cl-]>[Cl:22][CH2:3][C:4]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]2[C:7]([C@H:8]3[CH2:18][C@H:9]3[CH2:10][O:11]2)=[CH:6][CH:5]=1
Reactant: CC(=O)Cl
Reactant: COCc1ccc2c(c1C(=O)OC)OC[C@@H]1C[C@H]21
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Product: COC(=O)c1c(CCl)ccc2c1OC[C@@H]1C[C@H]21

Procedure:
Zinc chloride (0.014 g) was added to a solution of methyl cis-(1aRS,7bSR)-5-methoxymethyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 7, 0.53 g) and acetyl chloride (0.77 mL) in anhydrous diethyl ether (50 mL) and the resultant mixture was stirred for 1.5 hours. The mixture was washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give methyl cis-(1aRS,7bSR)-5-chloromethyl-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (0.486 g) as a gum.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:13]([N:15](CC)CC)[CH3:14].BrCC#N>CCOC(C)=O>[C:13]([CH2:14][O:11][C:10](=[O:12])[CH2:9][NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])#[N:15]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: N#CCBr
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC(=O)OCC#N
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution containing 2.0 g (11.4 mmol) of Nα-Boc-glycine in 25 mL of EtOAc was added 1.73 g (2.38 mL, 17.1 mmol) of triethylamine followed by 2.05 g (1.19 mL, 17.1 mmol) of bromoacetonitrile. The reaction mixture was stirred at 60° C. under an argon atmosphere for 16 h. The heterogeneous mixture was cooled to room temperature and filtered through a short pad of silica, washing with EtOAc to remove the precipitated triethylamine hydrobromide. The filtrate was concentrated under diminished pressure to give Nα-Boc-glycine cyanomethyl ester as a colorless syrup which solidified upon standing. The crude product was used directly in the next step without further purification: yield 2.12 g (87%); 1HNMR (500 MHz, CDCl3) δ 1.45 (s, 9H), 4.05 (d, 2H, J=5.5 Hz) and 4.79 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([CH3:11])[CH:9]=[N:8][C:5]2=[N:6][CH:7]=1.[NH2:12][C:13]1[C:22]2[C:17](=[C:18](Br)[C:19]([CH3:23])=[CH:20][CH:21]=2)[N:16]=[N:15][C:14]=1[C:25]([NH2:27])=[O:26]>>[NH2:12][C:13]1[C:22]2[C:17](=[C:18]([C:2]3[CH:3]=[C:4]4[N:10]([CH3:11])[CH:9]=[N:8][C:5]4=[N:6][CH:7]=3)[C:19]([CH3:23])=[CH:20][CH:21]=2)[N:16]=[N:15][C:14]=1[C:25]([NH2:27])=[O:26]
Reactant: Cc1ccc2c(N)c(C(N)=O)nnc2c1Br
Reactant: Cn1cnc2ncc(Br)cc21
Product: Cc1ccc2c(N)c(C(N)=O)nnc2c1-c1cnc2ncn(C)c2c1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 96 using 6-bromo-1-methyl-1H-imidazo[4,5-b]pyridine and 4-amino-8-bromo-7-methylcinnoline-3-carboxamide. 1H NMR (400 MHz, CD3OD) δ ppm 2.37 (s, 3 H), 3.98 (s, 3 H), 7.76 (d, J=9.09 Hz, 1 H), 8.09 (d, J=1.77 Hz, 1 H), 8.29 (d, J=8.59 Hz, 1 H), 8.39 (d, J=2.02 Hz, 1H), 8.47 (s, 1 H); ESI-MS m/z [M+H]+ 334.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH:32]4[CH2:35][O:34][CH2:33]4)[CH2:28][CH2:27]3)=[CH:22][N:21]=2)[C:5]2[N:9]=[CH:8][N:7](COCC[Si](C)(C)C)[C:6]=2[CH:18]=1>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([CH:32]4[CH2:35][O:34][CH2:33]4)[CH2:28][CH2:27]3)=[CH:22][N:21]=2)[C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:18]=1
Reactant: C[Si](C)(C)CCOCn1cnc2c(Nc3ccc(N4CCN(C5COC5)CC4)cn3)cc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Product: Clc1cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c2nc[nH]c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.8 %

Procedure:
A mixture of 118a (720 mg, 1.4 mmol) in TFA (10 mL) was stirred at room temperature for 6 h. The mixture was concentrated under reduced pressure and the diluted with water (10 mL). The pH of the mixture was adjusted to 7 by adding aqueous ammonia. It was then extracted with dichloromethane (3×20 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to afford 118b as a brown solid (500 mg, 93%). MS-ESI: [M+H]+ 385.1
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:12][C:9]1[CH:10]=[N:11][C:2]([O:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[CH:15]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: Oc1cccc(F)c1
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Cl)cnc1Oc1cccc(F)c1

Procedure:
To a stirred solution of methyl 2,5-dichloronicotinate (J. Med. Chem. 1993, 36, 2676, 353 mg, 1.71 mmol) and 3-fluorophenol (291 mg, 2.6 mmol) in toluene (5 mL) was added potassium carbonate (360 mg, 2.6 mmol) in one portion. The resulting mixture was heated at reflux temperature for 16 h with azeotroping using a Dean Stark apparatus. The mixture was poured into water (50 mL) and the aqueous mixture was extracted with ethyl acetate (100 mL). The organic extracts were washed with water (50 mL) and brine (50 mL), dried (sodium sulfate), and concentrated under reduced pressure to give crude methyl 5-chloro-2-(3-fluorophenoxy)nicotinate. To a stirred solution of the crude ester in methanol (10 mL) was added 2 N sodium hydroxide aqueous solution (2 mL). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was partitioned between ether (30 mL) and water (30 mL). The organic phase was separated and the aqueous phase was acidified with 2 N hydrochloric acid (10 mL). The acidic mixture was extracted with dichloromethane (50 mL×3). The combined organic layer was washed with brine (100 mL), dried (sodium sulfate), and concentrated to afford 448 mg (93%) of the title compound as off white solids: 1H-NMR (CDCl3) δ 8.44 (1H, d, J=2.6 Hz), 8.26 (1H, d, J=2.6 Hz), 7.46–7.36 (1H, m), 7.07–6.89 (3H, m); MS (ESI) m/z 268 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[C:18]2[C:17](=O)[O:16][N:15]=[C:14]([CH3:20])[C:13]=2[CH:12]=[C:11]([F:21])[C:10]=1[F:22]>CC(O)=O.[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[C:10]([F:22])=[C:11]([F:21])[CH:12]=[C:13]2[C:18]=1[C:17](=[O:16])[NH:15][CH:14]2[CH3:20]
Reactant: Cc1noc(=O)c2c(Nc3ccccc3Cl)c(F)c(F)cc12
Agent: [Zn]
Solvent: CC(=O)O
Product: CC1NC(=O)c2c1cc(F)c(F)c2Nc1ccccc1Cl
Yield: 73.8 %

Procedure:
A mixture solution of 8-(2-chlorophenylamino)-6,7-difluoro-4-methyl-benzo[d][1,2]oxazin-1-one (26 mg, 0.079 mmol) and Zn (30 mg, 0.46 mmol) in AcOH (2 mL) was heated for 1 hour at 85° C. The reaction mixture was filtered and the solid was washed with additional AcOH. The filtrate was concentrated in vacuo, diluted with EtOAc, and washed with saturated aqueous NaHCO3 and water. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give the desired product (18 mg, 74%) that was used directly without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][OH:28])=[O:24])[C:5]1=[O:29].C(N(C(C)C)CC)(C)C.Cl[C:40]([O:42][CH3:43])=[O:41].O>CN(C=O)C>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:11]2[CH:12]=[C:13]3[C:8]([C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][OH:28])=[O:24])[C:5](=[O:29])[N:4]3[CH2:3][CH2:2][NH:1][C:40](=[O:41])[O:42][CH3:43])=[N:9][CH:10]=2)=[CH:20][CH:19]=1
Reactant: NCCn1c(=O)c(C(=O)NCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Reactant: COC(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NCCn1c(=O)c(C(=O)NCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
A solution of 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(2-hydroxyethyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.0207 g, 0.052 mmol) and diisopropyl ethylamine (0.075 mL, 0.43 mmol) in DMF (2 mL) under nitrogen was treated with methyl chloroformate (0.0038 mL, 0.049 mmol) at ambient temperature. Water was added (2 mL) and the reaction was concentrated in vacuo. The resulting residue was purified by reversed phase HPLC to provide the title compound from pure fraction concentrated in vacuo as an off-white solid: 1H NMR (300 MHz, DMSO-D6) δ ppm 3.2 (m, 2 H), 3.4 (m, 5 H), 3.6 (m, 2 H), 4.1 (s, 2 H), 4.3 (t, J=6.3 Hz, 2 H), 4.9 (t, J=4.9 Hz, 1 H), 7.1 (t, J=8.9 Hz, 2 H), 7.3 (t, J=6.0 Hz, 1 H), 7.4 (m, 2 H), 8.1 (s, 1 H), 8.5 (s, 1 H), 10.4 (m, 1 H); ES+ MS: 459 (M+H+).
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[SH:26].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.[Cl-].[Na+].O>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26][CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]1
Reactant: Sc1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccccc2Cl)CC1
Temperature: 75 °C
Reaction time: 15 h

Procedure:
Tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (2.00 g, 7.16 mmol, prepared according to Blurton et al., WO 00/43362), 2-chlorobenzenethiol (0.898 ml, 7.88 mmol), and potassium carbonate (1.58 g, 11.5 mmol) were stirred together in acetonitrile (15 ml). The reaction was heated to 75° C. and was stirred at that temperature for 15 h. After cooling to room temperature, brine was added, and the mixture was extracted with EtOAc three times. Combined organic layers were dried over MgSO4, filtered and concentrated in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13]2[N:14]=[N:15][C:16]([C:20]([CH3:26])([CH3:25])[C:21]([O:23]C)=O)=[C:17](O)[N:18]=2)=[N:6]1.P(Cl)(Cl)(Cl)=O.[NH3:36]>C(#N)C>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13]2[N:14]=[N:15][C:16]3[C:20]([CH3:26])([CH3:25])[C:21](=[O:23])[NH:36][C:17]=3[N:18]=2)=[N:6]1
Reactant: COC(=O)C(C)(C)c1nnc(-c2nn(Cc3ccccc3F)c3c2CCC3)nc1O
Reactant: N
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4c3CCC4)nnc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
48 mg (0.06 mmol, purity 54%) of methyl 2-{3-[1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl]-5-hydroxy-1,2,4-triazin-6-yl}-2-methylpropanoate were admixed with 0.5 ml (5.36 mmol) of phosphoryl chloride and the mixture was stirred at RT for 2.5 h. The reaction solution was diluted with 10 ml of dry acetonitrile and gradually added dropwise while cooling with ice to 5 ml of a 25% aqueous ammonia solution, and the mixture was stirred at RT for 8 h. The reaction mixture was concentrated on a rotary evaporator and the residue was partitioned between dichloromethane/water. The organic phase was dried over sodium sulphate and concentrated on a rotary evaporator. The residue was purified by means of preparative HPLC (eluent: acetonitrile/water with 0.1% hydrochloric acid, gradient 20:80→100:0). 4.5 mg of the target compound were obtained (18% of theory).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH3:22])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:23][CH2:24][C:25](O)=[O:26])=[CH:5][C:4]=2[N:3]=1.ON1C2C=CC=CC=2N=N1.[CH3:38][N:39](C)[CH2:40]CCN=C=NCC.Cl.CNC>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH3:22])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:23][CH2:24][C:25]([N:39]([CH3:40])[CH3:38])=[O:26])=[CH:5][C:4]=2[N:3]=1
Reactant: COCc1nc2c(N)nc3cc(CCC(=O)O)ccc3c2n1CC(C)(C)O
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Product: COCc1nc2c(N)nc3cc(CCC(=O)N(C)C)ccc3c2n1CC(C)(C)O
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
3-[4-Amino-1-(2-hydroxy-2-methylpropyl)-2-(methoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]propanoic acid (1.25 g, 3.30 mmol), anhydrous pyridine (75 mL) and 1-hydroxybenzotriazole (892 mg, 6.60 mmol) were combined and the reaction was stirred for 30 minutes. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (1.27 g, 6.60 mmol) was added and the reaction mixture was stirred for an additional 15 minutes. Dimethylamine hydrochloride (540 mg, 6.60 mmol) was added in one portion and the reaction was stirred for an additional 4 hours. The solution was concentrated under reduced pressure and the resulting oil was dissolved in chloroform (50 mL) and washed with 1% aqueous sodium carbonate (3×25 mL). The combined aqueous washes were extracted with chloroform. The combined organic fractions were purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a CMA:chloroform gradient; 0-25% CMA over 1500 mL, followed by 25-30% CMA over 1000 mL) followed by recrystallization from acetonitrile to provide 931 mg of 3-[4-amino-1-(2-hydroxy-2-methylpropyl)-2-(methoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]-N,N-dimethylpropanamide as a white solid, mp 142-145° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:15]1([N:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C(OCC)(=O)C>[C:15]1([N:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)=[O:23])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: Nc1ccc(F)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Nc1ccc(F)cc1)N(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 69.6 %

Procedure:
To a solution of 4-fluoroaniline (0.2 g) in dichlbromethane (10 ml) were added in turn pyridine (0.19 ml) and diphenylcarbamoyl chloride (0.417 g) at 0° C. The mixture was allowed to warm to ambient temperature and stirred for 10 hours, and to the mixture was added N,N-dimethylaminopyridine (0.22 g), and the mixture was allowed to stir for another 1 hour. The reaction mixture was taken up into a mixture of water and ethyl acetate. The separated organic layer was washed in turn with hydrochloric acid (1N), aqueous sodium hydrogen carbonate and brine, and dried over magnesium sulfate. Evaporation under reduced pressure gave a residue, which was triturated with diisopropyl ether to give N,N-diphenyl-N′-4-fluorophenylurea (0.384 g).