Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:51]=[C:50]([O:52][CH3:53])[CH:49]=[C:48]([O:54][CH3:55])[C:4]=1/[CH:5]=[CH:6]/[CH:7]([S:19]([CH:22](/[CH:34]=[CH:35]/[C:36]1[C:41]([O:42][CH3:43])=[CH:40][C:39]([O:44][CH3:45])=[CH:38][C:37]=1[O:46][CH3:47])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([N+:31]([O-])=O)[CH:24]=1)(=[O:21])=[O:20])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([N+:16]([O-])=O)[CH:9]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].O>CC(C)=O.O>[CH3:55][O:54][C:48]1[CH:49]=[C:50]([O:52][CH3:53])[CH:51]=[C:3]([O:2][CH3:1])[C:4]=1/[CH:5]=[CH:6]/[CH:7]([S:19]([CH:22](/[CH:34]=[CH:35]/[C:36]1[C:37]([O:46][CH3:47])=[CH:38][C:39]([O:44][CH3:45])=[CH:40][C:41]=1[O:42][CH3:43])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([NH2:31])[CH:24]=1)(=[O:21])=[O:20])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([NH2:16])[CH:9]=1
Reactant: COc1cc(OC)c(/C=C/C(c2ccc(OC)c([N+](=O)[O-])c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c([N+](=O)[O-])c2)c(OC)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(N)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A solution of (E)-2,4,6-trimethoxystyryl-4-methoxy-3-nitrobenzylsulfone (1.3 mmol) in acetone-water (10:5) was heated to 50° C. After 30 min, sodium hydrosulfite (Na2S2O4) (26.3 mmol) was added slowly, and the mixture was heated at reflux (50° C., 1 h.), cooled to room temperature and water was added. The product was rinsed with NaHCO3, and then isolated by extraction with ethyl acetate. The organic layer was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the crude product was recrystallized from 2-propanol, m.p. 148-150° C.
Reaction SMILES: Cl.[CH2:2]([C:4]1[N:8]=[C:7]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[O:26][CH3:27])[S:18][C:14]=3[C:13](=[O:28])[N:12]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[C:11]2=[O:35])[O:6][N:5]=1)[CH3:3].[CH2:36]([O:38][C:39]1[C:48]([O:49][CH3:50])=[CH:47][C:46]2[C:45]([C:51]3[CH:59]=[CH:58][C:54]([C:55](O)=[O:56])=[CH:53][CH:52]=3)=[N:44][C@@H:43]3[CH2:60][CH2:61][S:62][CH2:63][C@@H:42]3[C:41]=2[CH:40]=1)[CH3:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:36]([O:38][C:39]1[C:48]([O:49][CH3:50])=[CH:47][C:46]2[C:45]([C:51]3[CH:52]=[CH:53][C:54]([C:55]([N:32]4[CH2:33][CH2:34][CH:29]([N:12]5[C:13](=[O:28])[C:14]6[S:18][C:17]([C:19]7[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=7[O:26][CH3:27])=[CH:16][C:15]=6[N:10]([CH2:9][C:7]6[O:6][N:5]=[C:4]([CH2:2][CH3:3])[N:8]=6)[C:11]5=[O:35])[CH2:30][CH2:31]4)=[O:56])=[CH:58][CH:59]=3)=[N:44][C@@H:43]3[CH2:60][CH2:61][S:62][CH2:63][C@@H:42]3[C:41]=2[CH:40]=1)[CH3:37]
Reactant: CCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccc(F)cc4OC)cc32)n1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccc(F)cc6OC)cc5n(Cc5nc(CC)no5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(3-Ethyl-1,2,4-oxadiazol-5-yl)methyl]-6-(4-fluoro-2-methoxyphenyl)-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (250 mg; compound B85) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (205 mg; compound C10) and HBTU (215 mg) in DCM (7 ml) in the presence of DIPEA (0.36 ml) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluation gradient: DCM/MeOH, 1/0 to 1/1 (v/v)] and preparative HPLC as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:7])=[CH:4][N:3]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(C(=O)OCc2ccccc2)cn1
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 6-aminonicotinic acid (100 g, 0.72 mol; Aldrich Chemical Company, Inc., Milwaukee, Wis.) in N,N-dimethylformamide (700 mL) with brisk mechanical stirring was added potassium carbonate (150 g, 1.08 mol) and the reaction was stirred for 10 min before the portionwise addition of benzyl bromide (95 mL, 0.80 mol). The reaction was stirred at room temperature overnight, then the solids were filtered off and washed thoroughly with ethyl acetate, and the solvent was removed under vacuum. The filter cake was dissolved in water and extracted with ethyl acetate. The residue after evaporation of N,N-dimethylformamide was combined with the ethyl acetate extracts (total volume 2 L of ethyl acetate) and the combined organic extracts washed with brine (5×500 mL), dried (MgSO4) and the solvent removed under reduced pressure. The crude product was refluxed with 1:1 diethyl ether:hexane for 30 min then the solids filtered off (warm), washed with diethyl ether:hexane (1:1), and dried. This solid was precipitated from hot toluene (hot filtration required to remove dibenzylated material) and dried to afford (I-28a) (107.2 g, 65%) as an off-white solid; 1H NMR (DMSO-d6): δ 8.50 (1 H), 7.82 (1 H), 7.34-7.29 (5 H), 6.84 (2 H), 6.43 (1 H), 5.23 (2 H); m/z 229.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][CH:16]=[C:17]([CH3:18])[C:10]=12.Cl[C:21]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[N:24]=[C:23]([NH2:34])[N:22]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>O>[F:1][C:2]1[CH:3]=[C:4]([NH:19][C:21]2[CH:26]=[C:25]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[N:24]=[C:23]([NH2:34])[N:22]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][CH:16]=[C:17]([CH3:18])[C:10]=12
Reactant: Cc1c[nH]c2nccc(Oc3ccc(N)cc3F)c12
Reactant: Nc1nc(Cl)cc(-c2ccc(F)cc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1c[nH]c2nccc(Oc3ccc(Nc4cc(-c5ccc(F)cc5)nc(N)n4)cc3F)c12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
180 mg (0.70 mmol) of {3-fluoro-4-[(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-phenyl}amine (from example XLII) and 191 mg (0.73 mmol) of 4-chloro-6-(4-fluorophenyl)pyrimidine-2-amine (from example LIX) are suspended in 10 ml of water. 101 μl of concentrated hydrochloric acid are added, and the mixture is stirred at 100° C. overnight. For work-up, the reaction solution is made alkaline using saturated sodium carbonate solution and extracted three times with ethyl acetate, and the extracts are dried over sodium sulfate and concentrated using a rotary evaporator. The residue is purified by preparative HPLC.
Reaction SMILES: [CH2:1]([Sn:9](Cl)(Cl)Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[Na+].[CH2:15]([CH:23]([SH:27])[C:24]([O-:26])=[O:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21].C([Sn](=O)CCCCCCCC)CCCCCCC>O>[CH2:15]([CH:23]([SH:27])[C:24]([O-:26])=[O:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]([CH3:21])[CH3:22].[CH2:15]([CH:23]([SH:27])[C:24]([O-:26])=[O:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]([CH3:21])[CH3:22].[CH2:15]([CH:23]([SH:27])[C:24]([O-:26])=[O:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]([CH3:21])[CH3:22].[CH2:1]([Sn+3:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC[Sn](Cl)(Cl)Cl
Agent: CC(C)CCCCCC(S)C(=O)[O-]
Agent: CCCCCCCC[Sn](=O)CCCCCCCC
Agent: [Na+]
Solvent: O
Product: CCCCCCCC[Sn+3]

Procedure:
Monooctyltin trichloride, 338.3 grams (1.0 mole), was added to a solution of 120.0 grams (3.0 moles) sodium hydroxide in 700 ml water, in a suitable reaction vessel, at such a rate that the exothermic reaction could be controlled at or below 75° C. This was followed by addition of 622.5 grams (3.0 moles) of isooctylthioglycolate. On continued stirring at or below 75° C., the reaction was deemed complete when all solid dioctyltin oxide hd been consumed. The resulting mixture was allowed to phase split. After discharging the aqueous by-product, vacuum stripping and filtering the resulting oily liquid, 851.2 grams of monooctyl tin tris(isooctylthioglycolate) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](O)=[O:8])([O-:3])=[O:2].Cl.O.[NH2:15][NH2:16]>CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH:15][NH2:16])=[O:8])([O-:3])=[O:2]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Reactant: NN
Agent: Cl
Solvent: CO
Solvent: O
Product: NNC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A mixture of 167g (1 mole) of m-nitrobenzoic acid and 160g (5 moles) of methanol was refluxed with stirring for 3 hours while a stream of dry HCl was bubbled in. A precipitate which formed on cooling to room temperature was filtered off, and dissolved in hot methanol. The solution was boiled for 10 minutes with a mixture of sodium carbonate and anhydrous calcium sulfate and was then filtered. The filtrate was stirred and refluxed while 118g (2 moles) of 85% hydrazine hydrate was added. The mixture was refluxed for 90 minutes and allowed to cool. The solid product was filtered off and recrystallized from water to give 258 g of m-nitrobenzhydrazide, m.p. 155°-155.5°C.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C>[NH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=2)[CH2:13][CH2:12]1
Reactant: CS(=O)(=O)Nc1ccc(OCC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc(OCC2CCNCC2)cc1

Procedure:
A solution of the product of part (iv) (0.15 g) in ethanol was hydrogenated at 50° and 3.5 bar in the presence of 5% palladium on carbon until the required amount of hydrogen had been absorbed. The catalyst was filtered off and washed several times with hot ethanol. The combined filtrate and washings were evaporated to give the product, (0.10 g), m.p. 180°-183°, which was used without further purification.
Reaction SMILES: [ClH:1].C(OC(=O)[N:8]([CH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=1)[CH2:9][CH2:10][NH:11][S:12]([C:15]1[C:16]2[CH:17]=[CH:18][N:19]=[CH:20][C:21]=2[CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:24]=1)(=[O:14])=[O:13])(C)(C)C>CO.ClCCl>[ClH:1].[ClH:1].[N+:40]([C:37]1[CH:38]=[CH:39][C:34]([CH2:33][CH2:32][CH2:31][NH:8][CH2:9][CH2:10][NH:11][S:12]([C:15]2[C:16]3[CH:17]=[CH:18][N:19]=[CH:20][C:21]=3[CH:22]=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:24]=2)(=[O:14])=[O:13])=[CH:35][CH:36]=1)([O-:42])=[O:41]
Reactant: CC(C)(C)OC(=O)N(CCCc1ccc([N+](=O)[O-])cc1)CCNS(=O)(=O)c1cc(-c2ccccc2)cc2cnccc12
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CCCNCCNS(=O)(=O)c2cc(-c3ccccc3)cc3cnccc23)cc1

Procedure:
Bubble gaseous HCl through a solution of [3-(4-Nitro-phenyl)-propyl]-[2-(7-phenyl-isoquinoline-5-sulfonylamino)-ethyl]-carbamic acid tert-butyl ester (1.9 g, 2.9 mmol) in methanol/dichloromethane (1:1) with cooling for 15 minutes. Remove the solvent under reduced pressure to afford the title compound as a foam.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]#[N:19])[CH2:7][CH2:6]1)=O.O.[NH2:21][NH2:22]>C(O)CCC>[C:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][C@H:8]1[CH2:9][CH2:10][C@H:5]([C:3]([NH:21][NH2:22])=[O:2])[CH2:6][CH2:7]1)#[N:19]
Reactant: NN
Reactant: COC(=O)[C@H]1CC[C@H](Oc2ccccc2C#N)CC1
Solvent: CCCCO
Solvent: O
Product: N#Cc1ccccc1O[C@H]1CC[C@H](C(=O)NN)CC1
Temperature: 120 °C

Procedure:
A mixture of trans-4-(2-cyano-phenoxy)-cyclohexanecarboxylic acid methyl ester (0.20 g, 0.77 mmol) and hydrazine hydrate (0.037 ml, 0.76 mmol) in n-butanol (0.5 ml) was heated at 120° C. for 22 h. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate (50 ml) and 1 M aqueous sodium hydroxide solution (50 ml). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (0.18 g, 90%) as white solid, which was used in the next step without further purification. MS m/e: 260 (M+H+)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([CH2:24][N:25]1[CH:29]=[CH:28][N:27]=[CH:26]1)=[CH:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=1)[C:11]([O:13]C)=[O:12].[OH-].[Na+]>CO>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([CH2:24][N:25]1[CH:29]=[CH:28][N:27]=[CH:26]1)=[CH:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=1)[C:11]([OH:13])=[O:12]
Reactant: COC(=O)c1cc(C=C(Cn2ccnc2)c2nccs2)cc(-c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(C=C(Cn2ccnc2)c2nccs2)cc(-c2ccccc2)c1
Yield: 68 %

Procedure:
A solution of methyl 3-[2-(thiazol-2-yl)-3-(imidazol-1-yl)prop-1-en-1-yl]-5-phenylbenzoate (Z isomer) (1.41 g; 3.5 mmol) in methanol (15 ml) was heated at reflux with 2N aqueous sodium hydroxide solution (4.4 ml; 8.79 mmol) for 5 hours. Methanol was then evaporated and the solution acidified to pH 6 with 6N HCl. The resulting precipitate was triturated with ethanol/ether to give 3-[2-(thiazol-2-yl)-3-(imidazol-1-yl)prop-1-en-1-yl]-5-phenylbenzoic acid as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2([CH3:14])[CH3:13].[Li]CCCC.CN([CH:23]=[O:24])C>C1COCC1>[Cl:12][C:10]1[CH:11]=[C:2]([CH:23]=[O:24])[CH:3]=[C:4]2[C:9]=1[O:8][CH2:7][CH2:6][C:5]2([CH3:14])[CH3:13]
Reactant: CC1(C)CCOc2c(Cl)cc(Br)cc21
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)CCOc2c(Cl)cc(C=O)cc21
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
6-Bromo-8-chloro-4,4-dimethyl-3,4-dihydro-2H-chromene (483 mg, 1.75 mmol) in THF (12.0 mL) under N2 atmosphere was cooled to −78° C., and n-BuLi (841 μL, 2.10 mmol) was added dropwise via a syringe. The reaction mixture was stirred at −78° C. for 10 minutes and then DMF (543 μL, 7.01 mmol) was added dropwise via a syringe. The resulting mixture was allowed to warm to room temperature and wet silica gel (5.0 g/0.5 mL of water) was added. The mixture was allowed to stir at room temperature for 10 minutes before it was filtered. The silica gel was rinsed with EtOAc, and the filtrate was concentrated under vacuum. The crude residue was purified by silica gel chromatography eluting with 0-20% EtOAc/hexanes to obtain the title compound as a white solid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[CH:32]=[C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][C@@H:44]([CH3:46])[N:43]([CH:47]4[CH2:50][O:49][CH2:48]4)[CH2:42][C@@H:41]3[CH3:51])=[CH:36][N:35]=2)[C:30](=[O:52])[N:29]([CH3:53])[CH:28]=1)(=O)C.[OH-].[Li+]>>[CH3:51][C@H:41]1[CH2:42][N:43]([CH:47]2[CH2:50][O:49][CH2:48]2)[C@H:44]([CH3:46])[CH2:45][N:40]1[C:37]1[CH:38]=[CH:39][C:34]([NH:33][C:31]2[C:30](=[O:52])[N:29]([CH3:53])[CH:28]=[C:27]([C:7]3[C:6]([CH2:5][OH:4])=[C:11]([N:12]4[CH2:24][CH2:23][N:15]5[C:16]6[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=6[CH:22]=[C:14]5[C:13]4=[O:25])[CH:10]=[C:9]([F:26])[CH:8]=3)[CH:32]=2)=[N:35][CH:36]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4C[C@@H](C)N(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Product: C[C@@H]1CN(c2ccc(Nc3cc(-c4cc(F)cc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Yield: 29.3 %

Procedure:
Following the procedures in Example 101i, hydrolysis of the acetate ester of 104p (288 mg, 0.40 mmol) with lithium hydroxide afforded 104 as a white solid (80 mg, 25%). LCMS: [M+H]+ 682. 1H NMR (500 MHz, CDCl3) δ 8.60 (d, J=2.0, 1H), 8.02 (d, J=2.5, 1H), 7.87 (d, J=1.5, 1H), 7.49-7.48 (m, 1H), 7.37 (d, J=9.0, 1H), 7.16 (d, J=9.0, 1H), 6.96 (d, J=8.5, 1H), 6.87 (s, 1H), 6.81 (d, J=9.0, 1H), 4.77-4.61 (m, 4H), 4.54 (d, J=11.5, 1H), 4.39-4.31 (m, 2H), 4.19-4.15 (m, 3H), 3.92-3.91 (m, 1H), 3.77-3.74 (m, 1H), 3.71 (s, 3H), 3.18 (s, 1H), 2.92-2.89 (m, 1H), 2.73-2.70 (m, 2H), 2.61-2.56 (m, 4H), 2.48 (s, 1H), 1.98-1.79 (m, 5H), 0.91-0.89 (m, 6H)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[O:4][NH2:5].[CH3:11][N:12]([CH3:16])[C:13](Cl)=[O:14].O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[O:4][NH:5][C:13](=[O:14])[N:12]([CH3:16])[CH3:11]
Reactant: CN(C)C(=O)Cl
Reactant: NOc1cc(Cl)ccc1Cl
Solvent: O
Solvent: c1ccncc1
Product: CN(C)C(=O)NOc1cc(Cl)ccc1Cl
Reaction time: 12 h
Yield: 61.9 %

Procedure:
5.00 g (28.1 mmoles) of 2,5-dichlorophenoxyamine was dissolved in 6.8 ml of pyridine, and then 3.02 g (28.1 mmoles) of dimethylcarbamoyl chloride was added. The mixture was stirred at a temperature of from 25° to 30° C. for 12 hours. After an addition of 200 ml of water, the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and precipitated crystals were washed with hexane, whereby 4.33 g of the desired product was obtained as light yellow crystals (yield: 62%).
Reaction SMILES: [C:1]([CH:4]([CH2:16][CH2:17][CH2:18][CH:19]([OH:28])[CH2:20][O:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])(=[O:3])[CH3:2].C(C(CCCC(O)COC1C=CC(F)=CC=1)CCCCCCC(O)=O)(=O)C>>[C:1]([CH:4]([CH2:16][CH2:17][CH2:18][CH:19]([OH:28])[CH2:20][O:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCCCCC(CCCC(O)COc1cccnc1)C(C)=O
Agent: CC(=O)C(CCCCCCC(=O)O)CCCC(O)COc1ccc(F)cc1
Product: CC(=O)C(CCCCCCC(=O)O)CCCC(O)COc1cccnc1

Procedure:
The synthesis of this compound is carried out by the procedure of Example 1, Step F, except that an equivalent quantity of ethyl 8-acetyl-12-hydroxy-13-(3-pyridyloxy)tridecanoate is substituted for the ethyl 8-acetyl-12-hydroxy-13-(4-fluorophenoxy)tridecanoate of Example 1, Step F.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[OH:15].C[O:17][C:18](O[Si](C)(C)C)=[C:19]([CH3:21])[CH3:20].Cl>CN(C=O)C.F[Zn]F>[C:8]([C:6]1[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]2[O:15][C:18](=[O:17])[C:19]([CH3:21])([CH3:20])[C:2]=2[CH:7]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: COC(O[Si](C)(C)C)=C(C)C
Reactant: CC(C)(C)c1cc(Br)c(O)cc1[N+](=O)[O-]
Agent: Cl
Agent: F[Zn]F
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc2c(cc1[N+](=O)[O-])OC(=O)C2(C)C
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Difluorozinc (6.093 g, 58.92 mmol) was added to a round bottomed flask, which was flushed with nitrogen. Pd(tBu3P)2 (2 g, 3.835 mmol) was then added under nitrogen stream. 2-Bromo-4-tert-butyl-5-nitro-phenol (16.15 g, 58.92 mmol) dissolved in DMF (80.75 mL) was then added to the flask. The reaction mixture was an orange suspension. (1-Methoxy-2-methyl-prop-1-enoxy)trimethylsilane (21.61 g, 25.13 mL, 117.8 mmol) was added to the mixture and the resulting mixture was heated to 80° C. and stirred for 16 h. When complete, the reaction mixture was cooled to ambient temperature and filtered through Celite®. The filter cake was washed with MTBE (536.0 mL) and water (893.3 mL) was added to the filtrate. The mixture was stirred for 15 min and settled for another 15 min. The layers were separated and 0.5M HCl (500 mL, 250.0 mmol) was added to the organic phase. The layers were separated and the organic layer was washed with water (500 mL). The layers were separated and the organic layer was washed with NaCl (500 mL; 8 wt %). The organic layer was separated and the solvent removed in vacuo. The crude product was obtained as a brown crystalline solid and was then purified through a silica plug, using hexane:MTBE 20:1-10:1 as an eluent. The fractions containing product were combined and the solvent removed in vacuo to give the pure product as a white crystalline solid. 1H-NMR (400 MHZ, DMSO-d6) δ 7.80 (s, 1H); 7.62 (s, 1H); 1.49 (s, 6H); 1.34 (s, 9H)
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].[Cl:11][CH2:12][C:13](Cl)=[O:14].Cl>C1(C)C=CC=CC=1>[Cl:11][CH2:12][C:13]([NH:1][C:2]1[O:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8])=[O:14]
Reactant: Cc1oc(N)c(C#N)c1C
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1oc(NC(=O)CCl)c(C#N)c1C
Yield: 122.3 %

Procedure:
20.4 g (0.1 mole) of 2-amino-3-cyano-4,5-dimethylfurane and 17.5 g (0.155 mole) of chloroacetyl chloride were boiled in 200 ml of toluene until the evolution of hydrogen chloride had subsided. Thereafter, the solvent was evaporated off under reduced pressure and the residue was recrystallized from ethyl acetate. 26 g of 2-chloroacetylamino-3-cyano-4,5-dimethylfurane of melting point 114° C. were obtained in this manner.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:16][CH2:17][CH2:18][O:19][CH2:20][C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH2:14])[C:5]=2[N:15]=1.[H][H]>[Pd].C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]([CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH2:14])[C:5]=2[N:15]=1
Reactant: [H][H]
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCOCC#Cc1ccccc1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: Cc1nc2c(N)nc3ccccc3c2n1CCCOCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2.75 h
Yield: 75.8 %

Procedure:
2-Methyl-1-{3-[(3-phenylprop-2-ynyl)oxy]propyl}-1H-imidazo[4,5-c]quinolin-4-amine (1.4 g, 3.779 mmol) was combined with toluene (15 mL) in a Parr flask and heated to reflux. The resulting solution was cooled to room temperature and purged with nitrogen. Palladium (0.6 g 10% palladium on carbon) was added to the solution under nitrogen, and the flask was pressurized with hydrogen at 310 kPa for 2.75 hours. Monitoring by HNMR indicated incomplete reaction. More 10% palladium on carbon (0.16 g) was added, and after an additional 2.5 hours at 310 kPA of hydrogen, the reaction was determined to be complete. The catalyst was filtered off, and the volatiles were removed under reduced pressure. The resulting white solid was recrystallized from acetonitrile and dried for 5 days to provide 1.0723 g of 2-methyl-1-[3-(3-phenylpropoxy)propyl]-1H-imidazo[4,5-c]quinolin-4-amine, m.p. 145.0-146.1° C.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[CH3:12][Si](C=[N+]=[N-])(C)C.N#N.C(OCC)(=O)C>CO.C1(C)C=CC=CC=1>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:12])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: N#N
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CBr)cc1
Temperature: 25 °C

Procedure:
To a solution of 1.0 eq of 4-(bromomethyl)benzoic acid in 20 ml of methanol and 50 ml of toluene; was added dropwise 2.05 eq of trimethylsilyldiazomethane while stirring at room temperature. The reaction was titrated until a persistant pale yellow color existed from the addition of excess trimethylsilyldiazomethane. Let stir at room temperature for 1 hr to insure the complete evolution of N2. Thin layer chromatography in 1:1 hexame:ethyl acetate indicated the disappearance of starting material and the appearance of desired ester with an Rf of 0.7.