Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(CN)O.Cl>O>[CH:8](=[C:7]1[NH:1][C:2](=[O:3])[NH:4][C:5]1=[O:6])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CNC(=O)N1
Agent: Cl
Solvent: O
Solvent: NCCO
Product: O=C1NC(=O)C(=Cc2ccccc2)N1
Temperature: 90 °C
Reaction time: 4 h
Yield: 89.8 %

Procedure:
50 g (0.5 mole) of hydantoin, 55 g (52 ml, 0.52 mole) of benzaldehyde and 46 g (45 ml, 0.7 mole of ethanol amine are admixed in 500 ml of water at 70° C. The temperature is raised to 90° C. and the reaction mixture is stirred for 4 hours. The solution is cooled and acidified with concentrated hydrochloric acid (pH 3-4). The mixture is allowed to stand at 10° C. for an hour, the product is filtered off, washed with cold water and dried. Thus 84.5 g of the desired compound are obtained, yield 89%. Mp.: 220°-222° C.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:22][O:23][C:24](=[O:36])[C:25]1[CH:34]=[CH:33][C:32]([NH2:35])=[C:27]([C:28]([O:30][CH3:31])=[O:29])[CH:26]=1.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:22][O:23][C:24](=[O:36])[C:25]1[CH:34]=[CH:33][C:32]([NH:35][C:17](=[O:18])[CH2:16][O:15][C:14]2[CH:13]=[CH:12][C:11]([C:1]34[CH2:10][CH:5]5[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]5)[CH2:8]3)[CH2:2]4)=[CH:21][CH:20]=2)=[C:27]([C:28]([O:30][CH3:31])=[O:29])[CH:26]=1
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: COC(=O)c1ccc(N)c(C(=O)OC)c1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)c(C(=O)OC)c1
Reaction time: 8 h
Yield: 73.6 %

Procedure:
To a mixture of (4-adamantan-1-yl-phenoxy)-acetic acid (229 mg, 0.8 mmol) and 4-aminoisophthalic acid dimethyl ester (301 mg, 1.4 mmol) were dissolved in DMF (5 mL), and EDCHCl (140 mg, 0.75 mmol), HOAt (163 mg, 1.2 mmol) and DIPEA (0.21 ml, 1.2 mmol) was added. The mixture was stirred overnight, and then partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4 anh), and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=50:1) to give 4-[2-(4-Adamantan-1-yl-phenoxy)acetyl-amino]-isophthalic acid dimethyl ester as a white solid (281 mg, 76.3% yield).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.Br[C:27]1[CH:28]=[C:29]2[C:35]([CH:36]([C:38]3[CH:39]=[C:40]4[C:45](=[CH:46][CH:47]=3)[N:44]=[CH:43][CH:42]=[CH:41]4)[CH3:37])=[N:34][O:33][C:30]2=[N:31][CH:32]=1.C([Sn](CCCC)(CCCC)[C:53]1[N:54]=[CH:55][S:56][CH:57]=1)CCC>CN(C=O)C>[S:56]1[CH:57]=[C:53]([C:27]2[CH:28]=[C:29]3[C:35]([C@@H:36]([C:38]4[CH:39]=[C:40]5[C:45](=[CH:46][CH:47]=4)[N:44]=[CH:43][CH:42]=[CH:41]5)[CH3:37])=[N:34][O:33][C:30]3=[N:31][CH:32]=2)[N:54]=[CH:55]1
Reactant: CC(c1ccc2ncccc2c1)c1noc2ncc(Br)cc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: CN(C)C=O
Product: C[C@H](c1ccc2ncccc2c1)c1noc2ncc(-c3cscn3)cc12
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a pressure vessel was added 2-(dicyclohexylphosphino)biphenyl (12 mg, 0.42 mmol), 6-(1-(5-bromoisoxazolo[5,4-b]pyridin-3-yl)ethyl)quinoline (0.10 g, 0.28 mmol), 4-(tributylstannyl)thiazole (0.16 g, 0.42 mmol) in anhydrous DMF (3 mL). The vial was flushed with argon, sealed and stirred at 90° C. for two hours. The mixture was concentrated and purified by MPLC (eluted with a gradient of 0 to 10% methanol in dichloromethane) to yield the racemic product as an off-white solid. The desired enantiomer (>99% ee) was obtained via SFC. MS m/z=359.0 [M+1]+ Calc'd for C20H14N4OS: 358.4
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][CH2:25][C:24]1=[O:43])[CH2:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:44]I>>[Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][CH:25]([CH3:44])[C:24]1=[O:43])[CH2:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cn1
Product: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)C(C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cn1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a −78° C. solution of 3.19 g (5.05 mmol) of (5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)piperidin-2-one (Example 121, Step I) and 347 μL (5.55 mmol) of methyl iodide in dry, degassed THF (40 mL) was added 6.82 mL (6.82 mmol) of a 1 M solution of lithium bis(trimethylsilyl)amide in THF slowly via syringe over 2 min. The yellow solution was warmed to 0° C. and stirred for 1.5 h, and then was warmed to room temperature and stirred for an additional 15 min. The reaction was quenched with saturated aqueous ammonium chloride, and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by flash chromatography on silica gel (0-15% MeOH/DCM, gradient elution) provided the title compound (mixture of C-3 epimers) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:18](=[O:19])[O:20][CH2:21][CH3:22])=[CH:10][CH:11]=1
Reactant: Nc1ccc(Oc2ccc(Cl)c(Cl)c2)cc1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(Oc2ccc(Cl)c(Cl)c2)cc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
4-(3,4-Dichlorophenoxy)benzenamine (0.1 mole) and pyridine (50 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer and thermometer and are cooled to about 5° C. Ethyl chloroformate (0.125 mole) is added, with stirring, at about 5° C. Stirring is continued for a period of about 30 minutes at about 5° C., then for an additional 16 hours at room temperature. The mixture is then washed with 2 portions of water (50 ml), dried and the solvent is then removed to yield the desired product ethyl [4-(3,4-dichlorophenoxy)phenyl]-carbamate.
Reaction SMILES: [NH2-].[Na+].[NH:3]1[CH2:8][CH2:7][O:6][CH:5]([CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][CH2:13][C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)[CH2:4]1.[CH2:25](Br)[CH3:26].O>C1C=CC=CC=1>[CH2:25]([N:3]1[CH2:8][CH2:7][O:6][CH:5]([CH2:9][N:10]2[C:11]3[CH:24]=[CH:23][CH:22]=[CH:21][C:12]=3[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=3)[CH2:4]1)[CH3:26]
Reactant: c1ccc2c(c1)CCc1ccccc1N2CC1CNCCO1
Reactant: CCBr
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCN1CCOC(CN2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium amide (0.08 g) in benzene was added a solution of 5-(2-morpholinylmethyl)-10,11-dihydro-5H-dibenz[b,f]azepine (0.5 g) in benzene under ice cooling, and the resulting mixture was stirred at room temperature for 30 minutes. to the reaction mixture was added a solution of ethyl bromide (0.22 g) in benzene under ice cooling, and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was cooled, admixed with water and extracted with benzene. The benzene extract was washed with water, dried over anhydrous sodium sulfate and evaporated to afford 5-(4-ethyl-2-morpholinylmethyl)-10,11-dihydro-5H-dibenz[b,f]azepine as an oily substance.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH2:12](O)[CH3:13].O=S(Cl)Cl>C(OCC)(=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: CCO
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(O)cc1

Procedure:
A mixture of 4-hydroxyphenylacetic acid (g.12 g, 0.06 mol), absolute ethanol (50 mL) and SOCl2 (2 mL, 0.028 mol) was refluxed for 3 hours. The residue was cooled, diluted with ethyl acetate (200 L), washed first with dilute aqueous sodium bicarbonate (100 mL) and then twice with water (100 mL), then was dried over anhydrous MgSO4, filtered and evaporated in vacuo. Ethyl 4-hydroxyphenylacetate was obtained as an oil.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([O:12][CH:13]([CH3:17])[C:14]([CH3:16])=[CH2:15])[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].[ClH:18].O>C(Cl)(Cl)(Cl)Cl.[Cl-].C([N+](CCCCCCCC)(CCCCCCCC)C)CCCCCCC>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([O:12][CH:13]([CH3:17])[C:14]([Cl:18])([CH3:16])[CH3:15])[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: C=C(C)C(C)Oc1cc(OCC#CC)ncn1
Reactant: Cl
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC#CCOc1cc(OC(C)C(C)(C)Cl)ncn1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
In 3 ml of carbon tetrachloride were dissolved 0.23 g of 4-(2-butynyloxy)-6-(1,2-dimethylallyloxy)pyrimidine and 0.01 g of trioctylmethylammonium chloride, to which 1 ml of concentrated hydrochloric acid was added dropwise at 0° C., followed by stirring at 0° C. for 30 minutes and at room temperature for 3 hours. The reaction mixture was then poured into water, which was extracted three times with t-butyl methyl ether. The combined organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution, a saturated aqueous sodium chloride solution, dried over anhydrous magnesium, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.05 g of 4-(2-butynyloxy)-6-(2-chloro-1,2-dimethylpropyloxy)pyrimidine (the present compound (34)).
Reaction SMILES: [CH2:1]([SH:5])[CH2:2][CH2:3][CH3:4].[CH:6]([CH:8]=[CH2:9])=[O:7]>N1CCCCC1>[CH2:1]([S:5][CH2:9][CH2:8][CH:6]=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS
Reactant: C=CC=O
Solvent: C1CCNCC1
Product: CCCCSCCC=O
Temperature: 25 °C
Reaction time: 36 h

Procedure:
n-Butyl mercaptan (1 mole) was stirred with 80-100 petroleum ether (150 ml) at 10° C and piperidine catalyst (0.02 gm) was added. To this, acrolein (1 mole) was added dropwise over a period of 2 hours. The reaction mixture was allowed to warm up to room temperature whereupon stirring was continued for a further 36 hours. The mixture was then distilled under reduced pressure to yield a β-n-butylmercaptopropionaldehyde fraction (0.92 mole) having a boiling range 55°-57° C at a pressure of 1-2 mm of Hg. The reaction mixture was maintained under a blanket of nitrogen at all time throughout the preparation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH2:11]1[CH:19]2[N:14]([CH2:15][CH2:16][C:17](=O)[CH2:18]2)[CH2:13][CH2:12]1>CC(=O)OCC>[CH2:11]1[CH:19]2[N:14]([CH2:15][CH:16]=[C:17]([C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)[NH:7][CH:6]=3)[CH2:18]2)[CH2:13][CH2:12]1
Reactant: O=C1CCN2CCCC2C1
Reactant: Clc1ccc2[nH]ccc2c1
Solvent: CCOC(C)=O
Product: Clc1ccc2[nH]cc(C3=CCN4CCCC4C3)c2c1

Procedure:
5-Chloro-1H-indole (1.00 g, 6.63 mmol) and 7-octahydroindolizinone (1.39 g, 9.95 mmol) were converted to product by the procedure of Preparation 17 to give 595 mg. (33.1%). EA calculated for C16H17N2Cl: C, 70.45; H, 6.28; N, 10.27. Found: C, 70.60; H, 6.46; N, 10.28. MS(FD) (m/e): 272.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:11]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)=[CH:12][C:13](OC)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].COC1C=C(C=CC=1OC)C(C1C=CC2OCOC=2C=1)=O.C(OP(CC#[N:58])(=O)OCC)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[CH3:26][O:25][C:19]1[CH:18]=[C:17]([C:11]([C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:10][O:2][C:3]=3[CH:4]=2)=[CH:12][C:13]#[N:58])[CH:22]=[CH:21][C:20]=1[O:23][CH3:24]
Reactant: COC(=O)C=C(c1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: COc1ccc(C(=O)c2ccc3c(c2)OCO3)cc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COc1ccc(C(=CC#N)c2ccc3c(c2)OCO3)cc1OC
Temperature: 25 °C

Procedure:
3-(3,4-Dimethoxyphenyl)-3 -(3,4-methylenedioxyphenyl)acrylonitrile was prepared analogously to methyl 3,3-bis-(3′,4′-dimethoxyphenyl)acrylate using 1-(3,4-dimethoxy-benzoyl)-3,4-methylenedioxybenzene (1.43 g, 5 mmol), diethylcyanomethylphosphonate (0.91 mL, 5.5 mmol) and lithium hexamethyldisilazide (4.2 mL, 5.5 mmol, 1.3 M) with a reaction time of 1 hour at reflux and 24 hours at room temperature. The crude product was purified by chromatography (silica gel, 2% ethyl acetate/methylene chloride) to afford 0.79 g (51%) of a mixture of the E and Z isomers as an off white solid: mp 121-123° C.; 1H NMR (CDCl3) δ 7.10-6.73 (m, 12 H), 6.13-5.94 (m, 4 H), 5.57 (s, 1 H), 5.53 (s, 1 H), 3.94 (s, 3 H), 3.92 (s, 3 H), 3.87 (s, 3 H), 3.84 (s, 3 H); 13C NMR (CDCl3) δ 162.3, 151.0, 150.5, 149.6, 149.1, 148.8, 148.5, 147.9, 133.2, 131.6, 130.8, 129.4, 124.3, 123.5, 123.1, 122.1, 118.5, 118.3, 112.6, 111.1, 110.7, 109.9, 108.5, 108.2, 101.6, 101.5, 92.2, 92.2, 56.0, 55.9, 55.9; Anal. Calcd for C18H15NO4. Theoretical: C, 69.89; H, 4.89; N, 4.53. Found: C, 69.61; H, 5.01; N, 4.37.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[S:4][C:3]=1/[CH:8]=[CH:9]/[C:10](N(C)C)=O.[N+]([O-])(O)=O.[N:19]1([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH2:34])=[NH:33])=[CH:27][CH:26]=2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[CH3:7][C:5]1[S:4][C:3]([C:8]2[CH:9]=[CH:10][N:34]=[C:32]([NH:31][C:28]3[CH:27]=[CH:26][C:25]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:30][CH:29]=3)[N:33]=2)=[C:2]([CH3:1])[N:6]=1
Reactant: Cc1nc(C)c(/C=C/C(=O)N(C)C)s1
Reactant: N=C(N)Nc1ccc(N2CCOCC2)cc1
Solvent: O=[N+]([O-])O
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)s1

Procedure:
By condensation between 3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone and N-(4-morpholin-4-yl-phenyl)-guanidine nitrate. Pale solid. 1H-NMR (CDCl3) δ: 2.69 (s, 3H, CH3), 2.70 (s, 3H, CH3), 3.14 (t, 4H, J=4.8 Hz, CH2), 3.72 (t, 4H, J=4.9 Hz, CH2), 6.89 (d, 1H, J=5.1 Hz, pyrimidinyl-H), 6.95 (d, 2H, J=8.8 Hz, Ph-H), 6.98 (br. s, 1H, NH), 7.53 (d, 2H, J=9.1 Hz, Ph-H), 8.38 (d, 1H, J=5.1 Hz, pyrimidinyl-H). MS (ESI+) m/z 368 [M+H]+ (C19H21N5OS requires 367.5).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: OB(O)c1ccccc1F
Reactant: COc1ccc2ccccc2c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc2ccccc2c1-c1ccccc1F
Yield: 60 %

Procedure:
Into a 500 mL three-neck flask were placed 8.7 g (35 mmol) of 1-bromo-2-methoxynaphthalene, and 5.0 g (35 mmol) of 2-fluorophenylboronic acid. The air in the flask was replaced with nitrogen. To this mixture were added 120 mL of toluene, 60 mL of ethanol, and 40 mL of an aqueous solution of sodium carbonate (2.0 mol/L). While the pressure was reduced; this mixture was stirred to be degassed. To this mixture was added 2.0 g (1.7 mmol) of tetrakis(triphenylphosphine)palladium(0), and the mixture was stirred at 80° C. for 8 hours under a nitrogen stream. The aqueous layer of the obtained mixture was subjected to extraction with toluene, and the obtained solution of the extract and the organic layer were combined and washed with saturated brine. The organic layer was dried over magnesium sulfate, and this mixture was gravity-filtered. An oily substance obtained by concentration of the obtained filtrate was dissolved in about 30 mL of toluene. This solution was suction-filtered through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), alumina, and Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135). An oily substance obtained by concentration of the obtained filtrate was dried under reduced pressure, so that 5.3 g of a pale yellow oily substance of the object of the synthesis was obtained in 60% yield. The above-described synthesis scheme is illustrated in the following scheme (C-1).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:25])=[C:4]2[C:9](=[CH:10][C:11]=1F)[N:8]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[F:20])[CH:7]=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:24].[NH:26]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH2:37][NH2:38])[CH2:27]1>>[NH2:38][CH2:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH:28]1[CH2:29][CH2:30][N:26]([C:11]2[CH:10]=[C:9]3[C:4]([C:5](=[O:24])[C:6]([C:21]([OH:23])=[O:22])=[CH:7][N:8]3[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])=[C:3]([CH3:25])[C:2]=2[F:1])[CH2:27]1
Reactant: Cc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2-c1ccc(F)cc1F
Reactant: NCc1ccccc1C1CCNC1
Product: Cc1c(F)c(N2CCC(c3ccccc3CN)C2)cc2c1c(=O)c(C(=O)O)cn2-c1ccc(F)cc1F
Yield: 72 %

Procedure:
Starting from 6,7-difluoro-1-(2,4 difluorophenyl)-1,4 dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid (0.40 g, 1.1 mmol) and 2-(3 pyrrolidinyl)benzenemethanamine, a procedure analogous to that given in Example 1, provided the title compound (0.40 g, 72%) as a beige solid, mp 283°-285° C. (dec).
Reaction SMILES: [F:1][C:2]1[C:28]([F:29])=[CH:27][C:5]2[N:6]([C@@H:9]3[O:26][CH2:25][C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]3[O:11][C:12](=[O:14])[CH3:13])[CH:7]=[N:8][C:4]=2[CH:3]=1.[Br:30]N1C(=O)CCC1=O>O1CCCC1>[Br:30][C:7]1[N:6]([C@@H:9]2[O:26][CH2:25][C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])[C:5]2[CH:27]=[C:28]([F:29])[C:2]([F:1])=[CH:3][C:4]=2[N:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1n1cnc2cc(F)c(F)cc21
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](OC(C)=O)CO[C@H]1n1c(Br)nc2cc(F)c(F)cc21
Yield: 77 %

Procedure:
The title compound was prepared according to General Procedure IV using 5,6-difluoro-1-(2,3,4-tri-O-acetyl-beta-D-ribopyranosyl)-1H-benzimidazole (1.1 g, 2.6 mmol), 60 ml tetrahydrofuran (Aldrich Sure Seal, Milwaukee), and a total of 2,8 g (16 mmol) of N-bromosuccinimide that was added in 3 ca. equivalent portions. The product from work-up by General Procedure IV was purified on a silica gel column (2.5×20 cm, 230-400 mesh) with hexanes and an increasing gradient from 5% to 20% ethyl acetate to give 1.0 g (2.0 mmol, 77% yield); MS (ES+): m/z (rel. intensity) 514 (1.0, M+23 (Na)); 1H NMR (DMSO-d6) δ8.26-8.21 (m, 1H), 7.73-7.69 (m, 1H), 5.93-5.91 (d, 1H, J=9.0 Hz), 5.69-5.62 (m, 3H), 4.11-3.90 (m, 2H), 2.20 (s, 3H), 1.98 (s,3H), 1.73 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[O:14])([O-:3])=[O:2].[H-].[Na+].Br[CH2:18][C:19]([O:21][CH3:22])=[O:20].Cl>CN(C=O)C.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:8](=[O:13])[C:7]2=[O:14])([O-:3])=[O:2]
Reactant: COC(=O)CBr
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2C1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CN1C(=O)C(=O)c2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A solution of 5-nitroindoline-2,3-dione (1 g, 5.20 mmol) in DMF (20 ml) was cooled to 0° C., and NaH (60% w/w dispersion in mineral oil, 0.208 g, 5.20 mmol) was added portion wise. The mixture was stirred at 0° C. for 1 hour, and methyl 2-bromoacetate (0.483 ml, 5.20 mmol) was added. The mixture was stirred at room temperature for 4 hours, then it was portioned between ethyl acetate and 1N HCl. The organic phase was washed twice with brine and dried over sodium sulfate. The solvent was removed and the crude was purified by flash chromatography on silica gel (DCM:EtOAc=95:5) affording methyl 2-(5-nitro-2,3-dioxoindolin-1-yl)acetate (0.976 g, 3.69 mmol, 71% yield) MS/ESI+ 264.9 [MH]+.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].S(=O)(=O)(O)O.O.OO.[CH2:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>[Cu].C(#N)C>[CH:21]1([O:1][N:2]2[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]2([CH3:12])[CH3:11])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CCCCC1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Agent: [Cu]
Agent: O=S(=O)(O)O
Agent: OO
Solvent: O
Solvent: CC#N
Product: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1
Yield: 70 %

Procedure:
Copper powder (0.060 g, 0.944 mmol) is added to a mixture of 5.00 g (29.0 mmol) of 1-oxyl-2,2,6,6-tetramethylpiperidin-4-ol, 44 ml of acetonitrile, and 30 ml of cyclohexane that has been heated to 40 degrees. A portion of a solution of 0.457 g of concentrated sulfuric acid in 3 mol of water is carefully added to the reaction mixture after the mixture is brought to reflux. To the refluxing reaction mixture is added dropwise over 2.5 hours a solution of 7.32 g (108 mmol) of 50% aqueous hydrogen peroxide. The remainder of the sulfuric acid solution is carefully added in portions to the reaction mixture during the first 15 minutes of the peroxide addition. After work up and purification according to the procedure of Example 54, the yield of the title compound is 5.22 g (70% yield), GC assay 94%.
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[CH2:3][N:4]1[C:16]2[C:15]3[C:14]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH3:26])=[CH:19][CH:18]=4)=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[CH:5]1.C(#[N:30])C>>[CH3:1][CH:2]([CH3:27])[CH2:3][N:4]1[C:16]2[C:15]3[C:14]([C:17]4[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][CH3:26])=[CH:21][CH:22]=4)=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:30])[C:7]=2[N:6]=[CH:5]1
Reactant: CC#N
Reactant: CCCOc1ccc(-c2cccc3ncc4ncn(CC(C)C)c4c23)cc1
Product: CCCOc1ccc(-c2cccc3nc(N)c4ncn(CC(C)C)c4c23)cc1
Reaction time: 36 h

Procedure:
The method described in Part J of Example 365 was used to oxidize and aminate 1-(2-methylpropyl)-9-(4-propoxyphenyl)-1H-imidazo[4,5-c]quinoline (1.1 g, 3.1 mmol). The amination reaction was stirred for 36 hours. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 70:30) to provide an oil, which was stirred with acetonitrile to provide a solid. The solid was isolated by filtration and recrystallized from acetonitrile to provide 165 mg of 1-(2-methylpropyl)-9-(4-propoxyphenyl)-1H-imidazo[4,5-c]quinolin-4-amine as light tan needles, mp 181-182° C.
Reaction SMILES: [CH:1]1([CH:6]([OH:10])[C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.N[C@H](C([C:17]1([NH2:40])[C:23](=[O:24])[N:22]([CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:21]2[CH:30]=[CH:31][CH:32]=[CH:33][C:20]=2[N:19]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:18]1=[O:39])=O)C>>[CH:1]1([CH:6]([OH:10])[C:7]([NH:40][C@H:17]([C:23]([NH:40][CH:17]2[C:18](=[O:39])[N:19]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:20]3[CH:33]=[CH:32][CH:31]=[CH:30][C:21]=3[N:22]([CH2:25][C:26]([CH3:28])([CH3:27])[CH3:29])[C:23]2=[O:24])=[O:24])[CH3:18])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C[C@H](N)C(=O)C1(N)C(=O)N(CC(C)(C)C)c2ccccc2N(CC(C)(C)C)C1=O
Reactant: O=C(O)C(O)C1CCCC1
Agent: Cl
Product: C[C@H](NC(=O)C(O)C1CCCC1)C(=O)NC1C(=O)N(CC(C)(C)C)c2ccccc2N(CC(C)(C)C)C1=O

Procedure:
Following General Procedure I above using cyclopentyl-α-hydroxyacetic acid (Example P) and 3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-(2,2-dimethylpropyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-V), the title compound was prepared as a white solid (melting point=119-129° C.). Purification was by flash chromatography eluting with CH2Cl2/EtOAc (1:1 gradient to 2:3). Rf=0.42 and 0.28 (CH2Cl2/EtOAc, 1:1).