Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-])=O)=[C:5]([CH3:10])[N:4]([CH2:11][CH2:12][OH:13])[N:3]=1>CCOC(C)=O.CCO.O=[Pt]=O>[NH2:7][C:6]1[C:2]([CH3:1])=[N:3][N:4]([CH2:11][CH2:12][OH:13])[C:5]=1[CH3:10]
Reactant: Cc1nn(CCO)c(C)c1[N+](=O)[O-]
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1nn(CCO)c(C)c1N
Temperature: 25 °C
Reaction time: 30 h

Procedure:
To a solution of 2-(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)ethanol (624 mg, 3.37 mmol) in EtOAc (1.2 mL, degassed) and EtOH (3.6 mL, degassed), PtO2 (66 mg, 0.34 mmol) was added and the reaction mixture was stirred at rt under a H2-atmosphere for 30 h. The mixture was diluted with EtOH, filtered over celite and the filter cake was rinsed with EtOH. The filtrate was concentrated to obtain 2-(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)ethanol as a pale brown solid, which was used in the next step without further purification. LC-MS conditions A: tR=0.16 min, [M+H]+=156.29.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1.[CH3:20][C:21]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:22]=1[NH2:23]>>[CH3:20][C:21]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:22]=1[NH:23][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1
Reactant: Clc1cc(-c2ccccn2)nc(-c2ccccn2)n1
Reactant: Cc1ccc(C)c(N)c1
Product: Cc1ccc(C)c(Nc2cc(-c3ccccn3)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from a mixture 4-chloro-2,6-di(2-pyridinyl)pyrimidine (25 mg, 0.093 mmol) and 2,5-dimethylaniline (17 μl, 0.140 mmol) similar to Example 111 and isolated as a yellow oil (7 mg, 21%). 1H NMR (CDCl3): 8.88-8.86 (m, 1H), 8.71-8.68 (m, 1H), 8.64-8.58 (m, 2H), 7.92-7.82 (m, 2H), 7.50 (s, 1H), 7.43-7.32 (m, 2H), 7.23 (s, 1H), 7.21 (d, J=7.5 Hz, 1H), 7.09 (s, 1H), 7.04 (dd, J=1.8, 7.8 Hz, 1H), 2.36 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: [CH3:1][O:2][P:3]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[N+:16]([O-])=O)(=[O:6])[O:4][CH3:5]>CO.[Ni]>[CH3:1][O:2][P:3]([C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[NH2:16])(=[O:6])[O:4][CH3:5]
Reactant: COP(=O)(OC)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: COP(=O)(OC)c1ccc(N)cc1N

Procedure:
113.5 g (0.479 mol) of 2,4-dinitro-benzene-phosphonic acid dimethyl ester (1) dissolved in 1500 ml of methanol are hydrogenated at 35° C and 60 excess atmospheres in the presence of 25 g of Raney nickel.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[F:16][C:17]([F:31])([CH3:30])[CH2:18][O:19][C:20]1[N:25]=[CH:24][C:23]([CH:26]([NH2:28])[CH3:27])=[CH:22][C:21]=1[CH3:29]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:28]([CH:26]([C:23]3[CH:24]=[N:25][C:20]([O:19][CH2:18][C:17]([F:31])([F:16])[CH3:30])=[C:21]([CH3:29])[CH:22]=3)[CH3:27])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(C(C)N)cnc1OCC(C)(F)F
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1OCC(C)(F)F
Yield: 64 %

Procedure:
The title compound is prepared in 64% yield (340 mg, brown oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (390 mg, 1.4 mmol, Step-1 of Intermediate-1) and 1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (374 mg, 1.4 mmol, Amine-56, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [C:1]([C:3]1[C:4]([I:17])=[C:5]([C:14]([OH:16])=[O:15])[C:6]([I:13])=[C:7]([C:11]=1[I:12])[C:8]([OH:10])=[O:9])#[N:2].S(=O)(=O)(O)[OH:19]>>[C:1]([C:3]1[C:11]([I:12])=[C:7]([C:8]([OH:10])=[O:9])[C:6]([I:13])=[C:5]([C:4]=1[I:17])[C:14]([OH:16])=[O:15])(=[O:19])[NH2:2]
Reactant: N#Cc1c(I)c(C(=O)O)c(I)c(C(=O)O)c1I
Reactant: O=S(=O)(O)O
Product: NC(=O)c1c(I)c(C(=O)O)c(I)c(C(=O)O)c1I
Temperature: 0 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
100 g of 5-cyano-2,4,6-triiodoisophthalic acid is suspended in 400 ml of concentrated sulfuric acid and heated first under agitation for 30 minutes to 60° C., then for 2 hours to 95° C. The thus-produced, clear solution is then poured on 1.2 kg of ice and stirred for one hour in an ice bath. The thus-precipitated crude product is vacuum-filtered, dissolved under heating in 400 ml of ethanol, and the solution is combined with 70 ml of concentrated sodium hydroxide solution. After several hours of agitation in an ice bath, the thus-separated sodium salt is vacuum-filtered, washed with ethanol, and then dissolved in 200 ml of hot water. After treating the solution with active carbon, the filtrate is precipitated into 150 ml of semiconcentrated sulfuric acid. After several hours of stirring in an ice bath, the precipitate is vacuum-filtered, washed with a small amount of ice-cold water, and dried at 50° C., thus obtaining 84 g (=82% of theory) of 5-carbamoyl- 2,4,6-triiodoisophthalic acid, which conforms in its properties with the product of the alkaline saponification.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[OH-].[Na+].[CH2:12]([O:19][C:20](Cl)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1.O.C1COCC1>[OH:1][C@H:2]1[CH2:6][N:5]([C:20]([O:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:21])[C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
A suspension of cis4-hydroxy-D-proline (10.0 g) in THF-water (1:1, 100 mL) was added 1N NaOH solution (50 mL) at 5° C. To the mixture was added a solution of benzyloxycarbonyl chloride (12.5 mL) in THF (10 mL) keeping pH to 8.5-10 by the addition of 2N NaOH solution at 5-10° C. After stirring at the same temperature for 1 h, the reaction mixture was washed with EtOAc (50 mL), adjusted to pH 2 by the addition of 4N HCl, and extracted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4), and evaporated in vacuo to give cis4-hydroxy-N-benzyloxycarbonyl-D-proline (18.74 g).
Reaction SMILES: FC1C(F)=C(F)C(F)=C2C=1[NH:4]C(=O)C(=O)N2.[Cl:17][C:18]1[C:19]([N+:31]([O-:33])=[O:32])=[C:20]2[C:25](=[CH:26][C:27]=1[Cl:28])[NH:24][C:23](=[O:29])[C:22](=[O:30])[NH:21]2.[OH-].[K+].NOS(O)(=O)=O>O>[NH2:4][N:24]1[C:25]2[C:20](=[C:19]([N+:31]([O-:33])=[O:32])[C:18]([Cl:17])=[C:27]([Cl:28])[CH:26]=2)[NH:21][C:22](=[O:30])[C:23]1=[O:29]
Reactant: O=c1[nH]c2c(F)c(F)c(F)c(F)c2[nH]c1=O
Reactant: O=c1[nH]c2cc(Cl)c(Cl)c([N+](=O)[O-])c2[nH]c1=O
Agent: NOS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nn1c(=O)c(=O)[nH]c2c([N+](=O)[O-])c(Cl)c(Cl)cc21
Reaction time: 0.17 h
Yield: 80 %

Procedure:
The procedure of Shin, S. C. and Lee, Y. Y., Taehan Hwahakhoe Chi 27 (5): 382-4 (1983) was adapted. A red solution of 6,7-dichloro-5-nitro-1,4-dihydro-2,3-quinoxalinedione (100 mg, 0.36 mMol, Cheeseman, supra) and 3N KOH (2 mL) in distilled water (5 mL) at 65° C. was dropwise added to a colorless solution of NH2OSO3H (75 mg, 0.66 mMol, Aldrich) in distilled water (0.5 mL) with stirring. A yellow precipitate came out after 10 mins. The mixture was stirred at 65° C. for 1 h and allowed to stand at room temperature overnight, then the precipitate was collected by filtration at 50° C. and was washed with distilled water (2 ml), then dried at 50° C. overnight, affording 85 mg (80% ) of crude 1-amino-5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione, as a yellow amorphous solid (80% of desired 1-amino-5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione with 20% starting material by NMR). A 85 mg sample of crude 1-amino-5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione (free base Na+, 0.293 mMol) was dissolved into distilled water (10 mL) at 50° C., then was acidified with AcOH to pH=5. After removal of the insoluble material by filtration, the mixture was heated at 60°-70° C. until a clear solution was obtained, which was slowly cooled, whereupon a yellow precipitate came out. The precipitate was crystallized from hot EtOH and the yellow microcrystals were collected by filtration, washed with cold ethanol (2 mL), and dried in the air at 60° C. for 4 h, affording 31 mg (29% ) of pure 1-amino-5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione. Mp was measured: the color of 1-amino-5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione changed to dark yellow at 275° C.; the decomposition of 1-amino-5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione is obvious at 280° C. and it melted to a black liquid at 290°-1° C. IR (KBr, cm-1): 3442; 3315; 3231; 1747; 1723; 1680; 1632; 1547. NMR (1H, DMSO-d6): δ 5.848 (s, 2H); 7.951 (s, 1H); 12,595 (s, 1H). HRMS: calcd for C8H4N4O4Cl2 (M+) m/z: 289.9623; found 289.9616.
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:7][O:6][C:5]([NH2:8])=[N:4][C@@:3]21[C:16]1[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=1)[CH2:10][CH2:9]2.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[CH:23][C:24]([C:27](O)=[O:28])=[N:25][CH:26]=1>>[NH2:8][C:5]1[O:6][CH2:7][C:2]([F:1])([F:18])[C@@:3]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:27](=[O:28])[C:24]4[CH:23]=[CH:22][C:21]([C:20]([F:30])([F:19])[F:31])=[CH:26][N:25]=4)[CH:15]=3)[CH2:10][CH2:9]2)[N:4]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cn1
Reactant: NC1=N[C@@]2(CCc3ccc(N)cc32)C(F)(F)CO1
Product: NC1=N[C@@]2(CCc3ccc(NC(=O)c4ccc(C(F)(F)F)cn4)cc32)C(F)(F)CO1
Yield: 15 %

Procedure:
The condensation of (R)-5′,5′-difluoro-2,3,5′,6′-tetrahydrospiro[indene-1,4′-[1,3]oxazine]-2′,6-diamine (intermediate A7.3) and 5-(trifluoromethyl)picolinic acid yielded the title compound (15% yield) as an off-white solid. MS (ISP): m/z=427.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:42]=[CH:41][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:37]=[CH:36][C:16]3[C:17](=[O:35])[CH2:18][C:19]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:20][C:15]=3[C:14]=2[CH2:38][CH2:39][CH3:40])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:37]=[CH:36][C:16]3[C:17](=[O:35])[CH2:18][C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[O:20][C:15]=3[C:14]=2[CH2:38][CH2:39][CH3:40])=[CH:41][CH:42]=1
Reactant: CCCc1c(OCCCOc2ccc([N+](=O)[O-])cc2)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Agent: [Ni]
Solvent: CCO
Product: CCCc1c(OCCCOc2ccc(N)cc2)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Reaction time: 3.25 h

Procedure:
A solution of 363 mg (0.62 mmol) of the title product of Example 38 in 45 ml of ethanol was treated with 36 mg of Raney nickel and then hydrogenated at atmospheric pressure and room temperature for 3.25 hr. The reaction mixture was filtered and the solvent was removed under reduced pressure. Chromotography of the residue over silica gel using 50-50 ethyl acetate/hexane as eluent gave the title compound as a white solid, m.p. 125.5°-127° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[C:13]([C:18](=[O:23])[C:19]([O:21][CH3:22])=[O:20])=[C:12](Cl)[N:11]3[CH:25]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:26]([O:29][C:30]1([CH3:59])[CH2:35][CH2:34][N:33](C2N3C=C(C4C=CC=C(Br)C=4)N=C3C=C(C)C=2C(=O)C(OC)=O)[CH2:32][CH2:31]1)[CH:27]=[CH2:28]>>[CH2:26]([O:29][C:30]1([CH3:59])[CH2:31][CH2:32][N:33]([C:12]2[N:11]3[CH:25]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=4)[N:9]=[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[C:13]=2[C:18](=[O:23])[C:19]([O:21][CH3:22])=[O:20])[CH2:34][CH2:35]1)[CH:27]=[CH2:28]
Reactant: C=CCOC1(C)CCN(c2c(C(=O)C(=O)OC)c(C)cc3nc(-c4cccc(Br)c4)cn23)CC1
Reactant: COC(=O)C(=O)c1c(C)c(C)c2nc(-c3cccc(Br)c3)cn2c1Cl
Product: C=CCOC1(C)CCN(c2c(C(=O)C(=O)OC)c(C)c(C)c3nc(-c4cccc(Br)c4)cn23)CC1
Yield: 60 %

Procedure:
Prepared from methyl 2-(2-(3-bromophenyl)-5-chloro-7,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-oxoacetate in 60% yield following the same procedure as methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-oxoacetate. LCMS (ESI, M+1): 540.20.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[H-].[Na+].[CH2:21](Br)[CH:22]=[CH2:23]>>[CH2:23]([N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[CH3:1])[C:7]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[N:8]1)[CH:22]=[CH2:21]
Reactant: C=CCBr
Reactant: COc1ccc(-c2n[nH]c3c(C)cccc23)cc1
Agent: [H-]
Agent: [Na+]
Product: C=CCn1nc(-c2ccc(OC)cc2)c2cccc(C)c21
Yield: 19.4 %

Procedure:
Prepared according to Method D step B from 7-methyl-3-(4-methoxyphenyl)-1H-indazole (0.112 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and allylbromide (0.086 mL, 1.0 mmol) to give the title compound (0.027 g) as a white solid. Used as is without further characterization.
Reaction SMILES: [Br-].[CH2:2]([C:4]1([O:9][C:10](=[O:34])[CH2:11][O:12][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([S+:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[C:22]4[CH:29]=[CH:30][CH:31]=[CH:32][C:21]3=4)=[CH:15][C:14]=2[CH3:33])[CH2:8][CH2:7][CH2:6][CH2:5]1)[CH3:3].[OH:35][C:36]12[CH2:45][CH:40]3[CH2:41][CH:42]([CH2:44][CH:38]([CH2:39]3)[CH2:37]1)[CH2:43]2.[Na].[C:47]([O:50][CH:51]([CH3:62])[C:52]([F:61])([F:60])[C:53]([F:59])([F:58])[S:54]([O-:57])(=[O:56])=[O:55])(=[O:49])[CH3:48].O>ClCCl>[OH:35][C:36]12[CH2:37][CH:38]3[CH2:44][CH:42]([CH2:41][C:40]([CH2:48][C:47]([O:50][CH:51]([CH3:62])[C:52]([F:61])([F:60])[C:53]([F:59])([F:58])[S:54]([O-:57])(=[O:56])=[O:55])=[O:49])([CH2:39]3)[CH2:45]1)[CH2:43]2.[CH2:2]([C:4]1([O:9][C:10](=[O:34])[CH2:11][O:12][C:13]2[C:14]([CH3:33])=[CH:15][C:16]([S+:20]3[C:21]4[CH:32]=[CH:31][CH:30]=[CH:29][C:22]=4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]3=4)=[CH:17][C:18]=2[CH3:19])[CH2:8][CH2:7][CH2:6][CH2:5]1)[CH3:3]
Reactant: CC(=O)OC(C)C(F)(F)C(F)(F)S(=O)(=O)[O-]
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: CCC1(OC(=O)COc2c(C)cc(-[s+]3c4ccccc4c4ccccc43)cc2C)CCCC1
Agent: [Br-]
Agent: [Na]
Solvent: ClCCl
Solvent: O
Product: CC(OC(=O)CC12CC3CC(CC(O)(C3)C1)C2)C(F)(F)C(F)(F)S(=O)(=O)[O-]
Yield: 89.1 %

Procedure:
5-(4-(2-(1-ethylcyclopentyloxy)-2-oxoethoxy)-3,5-dimethylphenyl)-5H-dibenzo[b,d]thiophenium bromide (2.00 g, 3.71 mmol) and sodium 3-hydroxyadamantane-acetoxy-1,1,2,2-tetrafluorobutane-1-sulfonate (1.61 g, 3.78 mmol) were dissolved in dichloromethane (100 mL) and water (100 mL) and stirred at r.t. overnight. The dichloromethane layer was separated and the aqueous phase washed with dichloromethane (3×100 mL). The combined organic layers were washed with water (4×200 mL), concentrated in vacuo and residual water removed via azeotrope with acetonitrile (2×200 mL) to afford the title compound (2.90 g, 91%) as a white solid. 1H NMR (500 MHz, (CD3)2CO) δ: 8.52 (d, J=8 Hz, 2H), 8.34 (d, J=8.5 Hz, 2H), 8.01 (t, J=7.5 Hz, 2H), 7.08 (t, J=7.5 Hz, 2H), 7.51 (s, 2H), 4.55 (s, 2H), 4.32 (t, J=6.5 Hz, 2H), 3.60 (brs, OH), 2.72 (tt, J=14, 6.5 Hz, 2H), 2.29 (s, 6H), 2.12-2.20 (m, 2H), 2.00 (q, J=7 Hz, 2H), 1.50-1.82 (m, 12H), 0.84 (t, J=7 Hz, 3H).
Reaction SMILES: [CH2:1]([C@H:8]([NH:37][C:38](=[O:48])[O:39][C@@H:40]1[C@H:47]2[C@H:43]([O:44][CH2:45][CH2:46]2)[O:42][CH2:41]1)[C@H:9]([OH:36])[CH2:10][N:11]([O:30][CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)[S:12]([C:15]1[CH:20]=[CH:19][C:18](OCCN2CCOCC2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:49]([O:52][CH2:53][CH3:54])(=O)[CH3:50]>>[CH2:1]([C@H:8]([NH:37][C:38](=[O:48])[O:39][C@@H:40]1[C@H:47]2[C@H:43]([O:44][CH2:45][CH2:46]2)[O:42][CH2:41]1)[C@H:9]([OH:36])[CH2:10][N:11]([O:30][CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35]1)[S:12]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([O:36][CH2:9][CH2:8][N:37]2[CH2:54][CH2:53][O:52][CH2:49][CH2:50]2)[CH:20]=1)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CN(OC1CCCC1)S(=O)(=O)c1ccc(OCCN2CCOCC2)cc1)O[C@H]1CO[C@H]2OCC[C@H]21
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CN(OC1CCCC1)S(=O)(=O)c1cccc(OCCN2CCOCC2)c1)O[C@H]1CO[C@H]2OCC[C@H]21

Procedure:
This compound was prepared from Example 44 under the same conditions used for the preparation of Example 98 (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-[(1S,2R)-1-benzyl-3-((cyclopentyloxy)[4-(2-morpholinoethoxy) phenyl]sulfonylamino)-2-hydroxypropyl]carbamate. Rf=0.15 (ethyl acetate); H1-NMR (CDCl3): δ7.44-7.14 (10H,m), 5.62 (1H,s), 5.00 (1H,m), 4.79 (2H,m), 4.16 (2H,m), 3.98-3.60 (10H,m), 3.12 (1H,bs), 3.02-2.71 (8H,m), 2.58 (4H,m), 1.90-1.72 (4H,m), 1.72-1.42 (4H,m); MS (ESI): M+H=690.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([CH:10]=[O:11])=[CH:8][CH:7]=[CH:6][N:5]2[CH:12]=1.[K+].[Br-:14]>>[Br:14][C:12]1[N:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH:10]=[O:11])[C:4]2=[N:3][C:2]=1[CH3:1]
Reactant: [Br-]
Reactant: Cc1cn2cccc(C=O)c2n1
Agent: [K+]
Product: Cc1nc2c(C=O)cccn2c1Br

Procedure:
From 4b (yield: 68%); mp 137-139° C.; IR (KBr) 1695, 1541 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.55 (s, 3H), 7.08 (t, 1H, J=7 Hz), 7.87 (d, 1H, J=7 Hz), 8.30 (d, 1H, J=7 Hz), 10.72 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 13.7, 94.6, 112.3, 123.3, 126.8, 128.4, 143.6, 143.7, 188.3; MS m/z 240 (M++2, 66), 238 (M+, 67), 212 (98), 210 (100), 131 (77), 104 (73), 78 (33), 51 (40).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:13][CH2:12][CH2:11][CH2:10][C:7]2([CH2:9][CH2:8]2)[CH:6]1[OH:14])=[O:4].C(N(CC)CC)C.[C:22](OC(=O)C)(=[O:24])[CH3:23].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]([CH:5]1[CH2:13][CH2:12][CH2:11][CH2:10][C:7]2([CH2:9][CH2:8]2)[CH:6]1[O:14][C:22](=[O:24])[CH3:23])=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)C1CCCCC2(CC2)C1O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)C1CCCCC2(CC2)C1OC(C)=O
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 4-hydroxy-spiro[2.6]nonane-5-carboxylic acid methyl ester (0.899 g) obtained in Step 2 in chloroform (18 mL) were added successively triethylamine (6.33 mL), 4-dimethylaminopyridine (0.11 g) and acetic anhydride (2.15 mL) under argon atmosphere and ice-cooling, followed by stirring the mixture at room temperature for 3.5 hours. After ice-cooling the reaction mixture and adding saturated aqueous sodium bicarbonate solution thereto, the reaction mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (diethyl ether:hexane (volume ratio)=1:9) to give 4-acetoxy-spiro[2.6]nonane-5-carboxylic acid methyl ester (1.06 g).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:20])[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])=[O:11]>C(O)(=O)C.S(=O)(=O)(O)O>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[O:11][C:4]2[C:3]([C:8](=[O:20])[CH:9]=1)=[CH:2][CH:7]=[CH:6][CH:5]=2
Reactant: COc1ccccc1C(=O)CC(=O)c1ccccc1O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COc1ccccc1-c1cc(=O)c2ccccc2o1
Temperature: 100 °C
Yield: 96.3 %

Procedure:
A solution of 1-(2-hydroxyphenyl)-3-(2-methoxyphenyl)-propan-1,3-dione (27 g, 0.1 mol) in acetic acid (130 ml) and concentrated sulfuric acid (5 ml) were placed in a flask fitted with a reflux condenser and a stirrer. The flask was heated in a bath maintained at 100° C. for an hour. Then the reaction mixture was poured onto crushed ice (750 g). The solid was filtered off, washed with water, dried and crystallized from methanol to give 24.3 g (96.2%) of the compound (m.p.: 97-98.5° C.). In the literature (J. Org. Chem., 27, 381 (1962)), 102-103° C. is given for the product melting point.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:23])[C:13]=2[N:12]=[C:11]1[CH2:24][CH2:25][CH2:26][CH3:27].[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[NH2:23][C:14]1[C:13]2[N:12]=[C:11]([CH2:24][CH2:25][CH2:26][CH3:27])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:35]([NH:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:36])[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCN
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCNC(=O)Nc1ccccc1

Procedure:
Using the general method of Example 145, 1-(8-aminooctyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.2 g, 3.26 mmol) was reacted with phenyl isocyanate to provide 1.59 g of N-[8-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)octyl]-N′-phenylurea as an off white powder, m.p. 153-155° C. Analysis: Calculated for C29H38N6O.0.20 H2O: %C, 71.05; %H, 7.89; %N, 17.14; Found: %C, 70.86; %H, 7.97; %N, 16.87. 1H NMR (300 MHz, DMSO-d6) δ 8.34 (s, 1H), 8.01 (d, J=7.8 Hz, 1H), 7.61 (dd, J=8.3, 1.0 Hz, 1H), 7.43-7.36 (m, 3H), 7.26-7.17 (m, 3H), 6.87 (t, J=7.3 Hz, 1H), 6.49 (s, 2H), 6.08 (m, 1H), 4.49 (m, 2H), 3.05 (m, 2H), 2.91 (m, 2H), 1.80 (m, 4H), 1.43-1.29 (m, 12H), 0.95 (t, J=7.3 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) 155.5, 153.4, 152.0, 144.9, 141.0, 132.6, 128.9, 126.7, 126.62, 126.57, 121.5, 121.2, 120.2, 117.9, 115.1, 45.1, 39.3, 30.1, 30.0, 29.0, 28.9, 26.6, 26.5, 26.2, 22.3, 14.1; MS m/z 487 (M+1)
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][C:17]2[N:16]=[CH:15][C:14]3[N:20]=[C:21]([CH2:35][O:36][CH2:37][CH3:38])[N:22]([CH2:23][C:24]([NH:27]C(=O)OC(C)(C)C)([CH3:26])[CH3:25])[C:13]=3[C:12]=2[CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)C>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][C:17]2[N:16]=[CH:15][C:14]3[N:20]=[C:21]([CH2:35][O:36][CH2:37][CH3:38])[N:22]([CH2:23][C:24]([NH2:27])([CH3:25])[CH3:26])[C:13]=3[C:12]=2[CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOCc1nc2cnc3ccc(OCc4ccccc4)cc3c2n1CC(C)(C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: CCOCc1nc2cnc3ccc(OCc4ccccc4)cc3c2n1CC(C)(C)N
Temperature: 25 °C
Yield: 93.2 %

Procedure:
A 50 mL solution of HCl in ethanol (4.3 M) was added to a solution of tert-butyl [2-(8-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]carbamate (8.4 g, 16.6 mmol) in ethanol (50 mL) and heated at reflux temperature for 1 hour. The reaction was cooled to ambient temperature and nitrogen was bubbled through the solution. The solvent was removed under reduced pressure and water was added to the residue. The solution was made basic and then extracted with three portions of dichloromethane. The combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated to yield 6.26 g of 2-(8-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethylamine as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][C@@:8]1([CH2:14][C:15]([O:17]C)=[O:16])[CH2:12][CH2:11][C@@H:10]([CH3:13])[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:1][O:5][C:6]([CH2:7][C@:8]1([CH2:14][C:15]([OH:17])=[O:16])[CH2:12][CH2:11][C@@H:10]([CH3:13])[CH2:9]1)=[O:19]
Reactant: COC(=O)C[C@]1(CC(=O)OC(C)(C)C)CC[C@@H](C)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C[C@]1(CC(=O)O)CC[C@@H](C)C1
Yield: 99.8 %

Procedure:
[(1S,3R)-1-Methoxycarbonylmethyl-3-methyl-cyclopentyl]-acetic acid tert-butyl ester (6.64 g, 24.6 mmol) and trifluoroacetic acid (10 mL) were stirred together in dichloromethane (30 mL) for 17 hours at room temperature. The mixture was carefully poured into aqueous sodium carbonate and extracted with ethyl acetate (200 mL). The aqueous was acidified to pH 1 with concentrated hydrochloric acid and re-extracted with ethyl acetate (3×200 mL), dried (MgSO4), and concentrated in vacuo. The residue was purified by chromatography (silica gel, eluting with a gradient of heptane to 1:1 heptane:ethyl acetate) to give 5.26 g (100%) of [(1R,3R)-1-methoxycarbonylmethyl-3-methyl-cyclopentyl]-acetic acid;