Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][N:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH:6]([N:11]([C:55]2[N:60]=[C:59](Cl)[N:58]=[C:57]([NH:62][CH2:63][CH2:64][CH2:65][CH2:66][CH:67]3[CH2:72][C:71]([CH3:74])([CH3:73])[N:70]([O:75][CH3:76])[C:69]([CH3:78])([CH3:77])[CH2:68]3)[N:56]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]([CH:43]2[CH2:48][C:47]([CH3:50])([CH3:49])[N:46]([O:51][CH3:52])[C:45]([CH3:54])([CH3:53])[CH2:44]2)[C:19]2[N:24]=[C:23](Cl)[N:22]=[C:21]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]3[CH2:36][C:35]([CH3:38])([CH3:37])[N:34]([O:39][CH3:40])[C:33]([CH3:42])([CH3:41])[CH2:32]3)[N:20]=2)[CH2:5][C:4]1([CH3:80])[CH3:79].[CH2:81]([CH2:83][NH2:84])[OH:82]>>[CH3:1][O:2][N:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH:6]([N:11]([C:55]2[N:60]=[C:59]([NH:84][CH2:83][CH2:81][OH:82])[N:58]=[C:57]([NH:62][CH2:63][CH2:64][CH2:65][CH2:66][CH:67]3[CH2:72][C:71]([CH3:74])([CH3:73])[N:70]([O:75][CH3:76])[C:69]([CH3:78])([CH3:77])[CH2:68]3)[N:56]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]([CH:43]2[CH2:48][C:47]([CH3:50])([CH3:49])[N:46]([O:51][CH3:52])[C:45]([CH3:54])([CH3:53])[CH2:44]2)[C:19]2[N:24]=[C:23]([NH:84][CH2:83][CH2:81][OH:82])[N:22]=[C:21]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]3[CH2:36][C:35]([CH3:38])([CH3:37])[N:34]([O:39][CH3:40])[C:33]([CH3:42])([CH3:41])[CH2:32]3)[N:20]=2)[CH2:5][C:4]1([CH3:80])[CH3:79]
Reactant: NCCO
Reactant: CON1C(C)(C)CC(CCCCNc2nc(Cl)nc(N(CCCCCCN(c3nc(Cl)nc(NCCCCC4CC(C)(C)N(OC)C(C)(C)C4)n3)C3CC(C)(C)N(OC)C(C)(C)C3)C3CC(C)(C)N(OC)C(C)(C)C3)n2)CC1(C)C
Product: CON1C(C)(C)CC(CCCCNc2nc(NCCO)nc(N(CCCCCCN(c3nc(NCCO)nc(NCCCCC4CC(C)(C)N(OC)C(C)(C)C4)n3)C3CC(C)(C)N(OC)C(C)(C)C3)C3CC(C)(C)N(OC)C(C)(C)C3)n2)CC1(C)C

Procedure:
The title compound is prepared from the reaction of N,N'-bis(1-methoxy-2,2,6,6-tetramethylpiperidin-4-yl)-N,N'-bis{2-chloro-4-[N-(1-methoxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazin-6-yl}-1,6-hexanediamine and ethanolamine.
Reaction SMILES: CCCCCCCCCCCC.Br[C:14]1[CH:15]=[N:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2.[C@@H]1(N)CCCC[C@H]1N.[CH3:32][O:33][C:34]([C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[NH:38][CH:37]=1)=[O:35].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:32][O:33][C:34]([C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]([C:14]2[CH:15]=[N:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:37]=1)=[O:35]
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: Brc1cnc2ccccc2c1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: CCCCCCCCCCCC
Solvent: C1COCCO1
Product: COC(=O)c1cn(-c2cnc3ccccc3c2)c2ccccc12
Temperature: 22 °C
Reaction time: 48 h
Yield: 79.4 %

Procedure:
5 cm3 of 1,4-dioxane, 230 cm3 of n-dodecane, 1.04 g (5 mmol) of 3-bromoquinoline and 0.6 cm3 (5 mmol) of trans-1,2-cyclohexanediamine are added at 22° C. under an argon atmosphere to 0.876 g (5 mmol) of 3-methoxycarbonyl-1H-indole, 2.23 g (10.51 mmol) of potassium orthophosphate and 0.09 g (0.5 mmol) of copper iodide. After stirring at 100° C. for 31 hours and after 48 hours at 22° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is diluted with 100 cm3 of ethyl acetate and then washed with 3 times 100 cm3 of water and 25 cm3 of saturated aqueous sodium chloride solution. After separating the phases by settling, the organic phase is dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 1.2 g of a residue which is purified by flash chromatography [eluent: cyclohexane/ethyl acetate (8/2 by volume)]. After concentrating the fractions under reduced pressure, 0.9 g of a yellow solid is obtained, which solid is recrystallised under hot conditions from a cyclohexane (6 cm3)/ethyl acetate (a few drops) mixture to give, after filtering off and drying under reduced pressure (2.7 kPa) at 40° C., 0.15 g of 3-methoxycarbonyl-1-(quinol-3-yl)-1H-indole in the form of a white solid melting at 138° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12]([N:15]3[CH2:19][CH2:18][CH2:17][C@H:16]3[C:20]([O:22]C(C)(C)C)=[O:21])(=[O:14])=[O:13])[CH:10]=2)[C:5]([Cl:27])=[CH:4][N:3]=1.O>Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12]([N:15]3[CH2:19][CH2:18][CH2:17][C@H:16]3[C:20]([OH:22])=[O:21])(=[O:14])=[O:13])[CH:10]=2)[C:5]([Cl:27])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Agent: Cl
Solvent: O
Product: O=C(O)[C@@H]1CCCN1S(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Reaction time: 3.5 h
Yield: 98.3 %

Procedure:
Hydrolysis ##STR42## tert-Butyl (2S)-1-[(1,4-dichloro-7-isoquinolinyl)sulfonyl]-2-pyrrolidinecarboxylate (50.0 g, 0.116 mol) was dissolved in conc. HCl (12 M, 200 ml) and stirred for 3.5 h. Water (200 ml) was added over 30 minutes and the resultant white precipitate stirred for a further 0.5 h, filtered and washed with water (3×100 ml). Drying under vacuum gave (2S)-1-[(1,4-dichloro-7-isoquinolinyl)sulfonyl]-2-pyrrolidinecarboxylic acid as a white solid (42.9 g, 0.114 mol).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:16])[NH:7][C:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:9][N:10]=1)[CH2:3][CH3:4].[CH:17]1([CH2:23][C:24](O)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:17]1([CH2:23][C:24]([NH:1][CH:2]([C:5]2[C:6](=[O:16])[NH:7][C:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[N:9][N:10]=2)[CH2:3][CH3:4])=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCC(N)c1nnc(C2CCCC2)[nH]c1=O
Reactant: O=C(O)CC1CCCCC1
Product: CCC(NC(=O)CC1CCCCC1)c1nnc(C2CCCC2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 58A, 150 mg (0.67 mmol) 6-(1-aminopropyl)-3-cyclopentyl-1,2,4-triazin-5(4H)-one, 96 mg (0.67 mmol) cyclo-hexylacetic acid and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][C@@:8]12[C:14]([CH3:16])([CH3:15])[C@@H:11]([CH2:12][CH2:13]1)C(C(O)=O)[C:9]2=[O:20]>CN(C)C=O.ClCCl>[CH3:7][C@@:8]12[C:14]([CH3:16])([CH3:15])[C@@H:11]([CH2:12][CH2:13]1)[CH:1]([C:2]([Cl:4])=[O:3])[C:9]2=[O:20]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2C(=O)Cl
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Oxalyl chloride (34 mL, 390 mmol) and N,N-dimethylformamide (4-5 drops) were added sequentially to a solution of (1S,4S)-3-camphorcarboxylic acid (Intermediate 24; 25.75 g, 131 mmol) in dichloromethane (130 mL) at 0° C. The reaction mixture was stirred at 0° C. for 20 min and then at room temperature for 2.5 h. The solvent was evaporated, and the residue was co-evaporated four times with dichloromethane and then dried under high vacuum to give crude (1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride. The crude acid chloride was dissolved in dichloromethane (340 mL) at 0° C., and triethylamine (42 mL, 301 mmol) was added. The mixture was stirred at 0° C. for 5 min, and then N′-(2,4-difluoro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (Intermediate 32; 24.5 g, 100.4 mmol) was added. The mixture was stirred at 0° C. for 5 min, at reflux for 2.5 h, and then at room temperature for 2 days. Dichloromethane (250 mL) and water (250 mL) were added and the layers were separated. The aqueous layer was extracted with dichloromethane (2×100 mL) and the combined organic layers were dried (magnesium sulfate), filtered and evaporated to give crude N′-(2,4-difluoro-phenyl)-N′-((1S,4S)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (66.5 g, 157% of the expected amount) as a black oil which was used directly in the next step.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([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.[Cl:20][CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25]>C1COCC1>[Cl:20][CH2:21][CH2:22][CH2:23][C:24]([N:17]1[CH2:18][CH2:19][N:14]([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:15][CH2:16]1)=[O:25]
Reactant: O=C(Cl)CCCCl
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: C1CCOC1
Product: O=C(CCCCl)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
25 g (99 mmol) benzhydrylpiperazine and 15.2 ml (109 mmol) TEA are present in 200 ml absolute THF and cooled to ca. 0° C. under moisture exclusion. 14 g (99 mmol) 4-chlorobutyric chloride are dissolved in 40 ml absolute THF and added dropwise. The mixture is stirred an additional three hours at RT and subsequently filtered. The filtrate is concentrated under vacuum, the residue is taken up in acetic acid ethyl ester and washed with saturated NaCl solution. The organic phase is dried over sodium sulfate and concentrated under vacuum until dry. The resin is further processed without further purification: yield 35.1 g (99%).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=O)O.N[C@H]([C:13]([OH:15])=[O:14])C>>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][C:13](=[O:14])[OH:15]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: C[C@H](N)C(=O)O
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
A4Glu, Asp, Pro, or Ala;
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.Cl.[CH3:20][C:21]1([CH3:34])[N:25]([CH2:26][CH2:27][NH:28][C:29]([NH2:31])=[NH:30])[C:24](=[O:32])[NH:23][C:22]1=[O:33].[OH-].[Na+].CC(O)C>ClCCl.O>[CH3:20][C:21]1([CH3:34])[N:25]([CH2:26][CH2:27][NH:28][C:29]2[N:31]=[C:5]([C:7]3[S:8][CH:9]=[CH:10][C:11]=3[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:4]=[CH:3][N:30]=2)[C:24](=[O:32])[NH:23][C:22]1=[O:33]
Reactant: CC1(C)C(=O)NC(=O)N1CCNC(=N)N
Reactant: CN(C)C=CC(=O)c1sccc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: ClCCl
Solvent: O
Product: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2sccc2-c2ccccc2)n1
Reaction time: 18 h
Yield: 33 %

Procedure:
A flask charged with 3-(dimethylamino)-1-(3-phenylthiophen-2-yl)prop-2-en-1-one (52 mg, 0.20 mmol), 1-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)ethyl)guanidine hydrochloride (100 mg, 0.40 mmol) and sodium hydroxide (40 mg, 1.0 mmol) and IPA (3.0 mL) was heated to reflux under nitrogen. After 18 h, the reaction mixture was allowed to cool and then diluted with dichloromethane and water. The organic layer was separated and washed with one portion of water and two portions of brine. The organics were then concentrated and the residue purified by preparative TLC eluted with 3% MeOH/dichloromethane to afford the product (27 mg, 0.066 mmol, 33% yield). MS (M+H)+ 408.
Reaction SMILES: NC1(N)[C:10]2[C:5](=[CH:6]C=CC=2)[CH2:4]C1.[NH2:12][C:13]1[C:14]([CH3:25])=[C:15]2[C:19](=[C:20]([NH2:22])[CH:21]=1)[C:18]([CH3:24])([CH3:23])[CH2:17][CH2:16]2>>[NH2:12][C:13]1[C:14]([CH3:25])=[C:15]2[C:19](=[C:20]([NH2:22])[C:21]=1[C:5]([CH3:10])([CH3:6])[CH3:4])[C:18]([CH3:23])([CH3:24])[CH2:17][CH2:16]2
Reactant: NC1(N)CCc2ccccc21
Reactant: Cc1c(N)cc(N)c2c1CCC2(C)C
Product: Cc1c(N)c(C(C)(C)C)c(N)c2c1CCC2(C)C

Procedure:
The diaminoindane derivative of claim 2 wherein the derivative if 5,7-diamino-1,1,4-trimethylindane.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][C:13]1([OH:28])[CH2:24][CH2:25][CH2:26]O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:13]2([O:28][CH2:26][CH2:25][CH2:24]2)[CH2:14][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](NC(=O)OCc2ccccc2)C(O)(CCCO)C1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](NC(=O)OCc2ccccc2)C2(CCCO2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 41.9 %

Procedure:
To a solution of 0.80 g of the diol of step D in 15 mL of dichloromethane at 0° C. were added 0.2 mL of methanesulfonyl chloride and 0.8 mL of triethylamine. After being stirred for 1 hour, the mixture was refluxed at 60° C. overnight. Solvent was removed under vacuum. The residue was taken up in EtOAc/water and the two phases were separated. The water phase was extracted with EtOAc twice. The combined organic was dried over Na2SO4. Solvent was removed under vacuum. Column chromatography on silica gel using 15% EtOAc/hexane to 100% EtOAc as eluent provided 0.32 g of the title compound. MS (M+H)+ 377.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH:22]([F:24])[F:23])=[C:18]([F:25])[CH:17]=3)[O:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:27][C:28]1[N:29]=[C:30]2[S:37][CH:36]=[C:35]([CH3:38])[N:31]2[C:32](=[O:34])[CH:33]=1.O.OC1N=CN=C2C=1NC(S)=N2>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH:22]([F:24])[F:23])=[C:18]([F:25])[CH:17]=3)[O:11][C:10](=[O:12])[C:9]([CH2:27][C:28]3[N:29]=[C:30]4[S:37][CH:36]=[C:35]([CH3:38])[N:31]4[C:32](=[O:34])[CH:33]=3)=[C:8]([OH:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1csc2nc(CCl)cc(=O)n12
Reactant: O=C1CC(=O)OC(CCc2ccc(C(F)F)c(F)c2)(C2CCCC2)C1
Agent: Oc1ncnc2nc(S)[nH]c12
Solvent: O
Product: Cc1csc2nc(CC3=C(O)CC(CCc4ccc(C(F)F)c(F)c4)(C4CCCC4)OC3=O)cc(=O)n12

Procedure:
The title compound was prepared as described in Example B(54) where 6-Cyclopentyl-6-{2-[4-(difluoromethyl)-3-fluorophenyl]ethyl}-dihydro-2H-pyran-2,4(3H)-dione (described in Step 3 of Example B(69)) was used in place of 6-[2-(5-Chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 7-(Chloromethyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (prepared according to a reported procedure: Doria, G.; Passarotti, C.; Sala, R.; Magrini, R.; Sberze, P.; Tibolla, M.; Cesarani, R.; Arcari, G.; Castello, R.; Toti, D. Farmaco Ed. Sci. 1985, 40, 885) was used in place of 6-Hydroxy-8-mercaptopurine monohydrate.
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5]1)([OH:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[O:9]=[C:6]1[CH2:7][CH2:8][CH:4]([C:1]([O:3][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:2])[CH2:5]1
Reactant: O=C1CCC(C(=O)O)C1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCC(C(=O)OCc2ccccc2)C1
Reaction time: 4 h

Procedure:
To a solution of 3-carboxycyclopentanone (640 mg, 5.0 mmol) in 8 mL of degassed DMF was added potassium carbonate (828 mg, 5.99 mmol) and benzyl bromide (0.65 mL, 5.49 mmol). After 4 hours at room temperature, the reaction mixture was poured into 50 mL of water and extracted 3 times with EtOAc. The combined organic layers were washed with water and dried over sodium sulfate. Filtration and solvent removal provided material that was subjected to silica gel chromatography eluting with 10% EtOAc in hexanes to yield benzyl 3-oxocyclopentanecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[C:21](Cl)[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:19]3[Cl:33])([C:10]2[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=2)[OH:9])=[CH:4][CH:3]=1.[OH:34][CH2:35][CH2:36][NH:37]C(=O)C(F)(F)F.C1(C)C=CC=CC=1.[H-].[Na+]>CCOC(C)=O>[NH2:37][CH2:36][CH2:35][O:34][C:21]1[C:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[C:19]([Cl:33])[C:18]2[C:23](=[CH:24][CH:25]=[C:16]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([C:10]3[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=3)[OH:9])[CH:17]=2)[N:22]=1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Reactant: O=C(NCCO)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(OCCN)c(-c3ccccc3)c(Cl)c2c1
Temperature: 25 °C

Procedure:
(4-Chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol (100 mg, 0.202 mmol, Example 65), N-(2-hydroxyethyl)-2,2,2-trifluoroacetamide (49 mg, 0.30 mmol), toluene (2 mL), and sodium hydride (60% dispersion in mineral oil, 32.3 mg, 0.808 mmol) were combined in a round bottom flask and heated at reflux for 48 hours under an N2 atmosphere. Analysis after overnight reaction showed only partial conversion, so additional N-(2-hydroxyethyl)-2,2,2-trifluoroacetamide (33 mg, 0.21 mmol) and sodium hydride (60% dispersion in mineral oil, 25 mg, 1.03 mmol) were added and the vessel was resealed and heated at reflux for an additional 48 hours. The reaction solution was then cooled to room temperature, diluted with EtOAc, transferred to a separatory funnel, and extracted with saturated, aqueous NH4Cl then saturated, aqueous NaHCO3 solutions. The organic phase was separated then dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified via reverse phase chromatography using acetonitrile with 0.05% trifluoroacetic acid in water as eluent. The fractions from the purification containing the desired product were transferred to a separatory funnel with EtOAc and extracted with a saturated, aqueous NaHCO3 solution. The aqueous layer was separated, extracted with EtOAc, then the combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound. MS (ESI): mass calcd. for C28H24Cl2N4O2, 518.1; m/z found, 519.2 [M+H]+; 1H NMR (600 MHz, CD3OD) δ ppm 8.17 (d, J=2.0 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.72 (dd, J=8.8, 2.1 Hz, 1H), 7.69 (s, 1H), 7.50-7.45 (m, 2H), 7.44-7.40 (m, 1H), 7.39-7.33 (m, 6H), 6.26 (s, 1H), 4.67-4.60 (m, 2H), 3.47 (s, 3H), 3.20 (t, J=5.3 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:7]2[C:12]([C:13](=[O:26])[C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([O:24]C)=[O:23])=[CH:18][CH:17]=1)=[CH:11][CH:10]=[C:9]([Cl:27])[CH:8]=2)=[O:4].[OH-].[Li+].Cl.C(OC)(=O)C>O1CCOCC1.O>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:7]2[C:12]([C:13](=[O:26])[C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][CH:17]=1)=[CH:11][CH:10]=[C:9]([Cl:27])[CH:8]=2)=[O:4]
Reactant: COC(=O)c1ccc(Cc2c(C(=O)OC)n(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: COC(C)=O
Product: COC(=O)c1c(Cc2ccc(C(=O)O)cc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 25 °C
Yield: 83.4 %

Procedure:
A 2 L three necked round bottom flask equipped with a mechanical stirrer, a nitrogen bubbler and a thermometer was charged with 7-chloro-3-(4-methoxycarbonyl-benzyl)-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (34 g, 73.6 mmol) methanol (600 mL) and 1,4-dioxane (300 mL). The resulting mixture was treated with lithium hydroxide (3.52 g, 146 mmol). The reaction was stirred at 25° C. over the weekend. At this time, the reaction was warmed to 35° C. and was stirred at 35° C. overnight. The reaction was then treated with additional lithium hydroxide (3.5 g, 1.46 mmol) and water (10 mL) and continued to stir at 35° C. overnight. At this time, additional 1,4-dioxane (300 mL) was added to the reaction. The reaction was stirred at 35° C. overnight. The reaction was then warmed to 40° C. where it stirred for 8 h and then was stirred at 35° C. overnight. At this time, the reaction was cooled to 25° C., treated with concentrated hydrochloric acid (25 mL) and methyl acetate (500 mL) and concentrated in vacuo. The resulting solids were collected by filtration, washed with methanol and dried in vacuo to afford 3-(4-carboxy-benzyl)-7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (27.5 g). An additional amount of 3-(4-carboxy-benzyl)-7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (3 g, total yield: 92.5%) was obtained through concentration of the filtrate and collection of the resulting solids. This material was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:10][CH:9]=1.Br[CH2:24][CH2:25][CH2:26][CH3:27]>>[CH2:24]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[CH:10][CH:9]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCBr
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2ccccc2O)cc1
Product: CCCCOc1ccccc1-c1ccc(CNC(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 20 using tert-butyl N-(2′-hydroxybiphenyl-4-ylmethyl)carbamate instead of tert-butyl N-(3′-hydroxybiphenyl-4-ylmethyl)carbamate and 1-bromobutane instead of 1-bromopropane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][S:10]([NH2:13])(=[O:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.Cl[C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])[CH:18]=[CH:17][N:16]=1>>[CH3:28][O:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:19]1[CH:18]=[CH:17][N:16]=[C:15]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][S:10]([NH2:13])(=[O:11])=[O:12])[CH:5]=[CH:6][CH:7]=2)[CH:20]=1
Reactant: COc1ccccc1-c1ccnc(Cl)c1
Reactant: Nc1cccc(CCS(N)(=O)=O)c1
Product: COc1ccccc1-c1ccnc(Nc2cccc(CCS(N)(=O)=O)c2)c1
Yield: 2.3 %

Procedure:
H1 was prepared from A6 (92 mg, 0.46 mmol) and A1 (100 mg, 0.46 mmol) following the procedure reported for G1 and obtained as a pale yellow amorphous solid (4 mg, 2%). 1H NMR (400 MHz, d6-DMSO, 300K) δ 2.95-3.03 (m, 2H), 3.21-3.29 (m, 2H), 3.81 (s, 3H), 6.87 (bs, 2H), 6.93-7.01 (m, 2H), 7.07 (t, J=7.5 Hz, 1H), 7.10-7.14 (m, 1H), 7.16 (d, J=8.5 Hz, 1H), 7.29 (t, J=8.0 Hz, 1H), 7.36-7.47 (m, 4H), 8.07 (d, J=5.4 Hz, 1H), 9.67 (bs, 1H). MS (ES) C20H21N3O3S requires: 383. found: 384 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[Cl:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:20]=[C:19]([Cl:31])[C:18]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:20]=[C:19]([Cl:31])[C:18]=1[O:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: Oc1c(Cl)cc(OCc2ccccc2)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2c(Cl)cc(OCc3ccccc3)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.9 %

Procedure:
A stirred solution of 10.0 grams (0.046 mole) of tert-butyl 4-(hydroxymethyl)piperidinecarboxylate (commercially available) and 12.5 grams (0.046 mole) of 2,6-dichloro-4-(phenylmethoxy)phenol (known compound) in 100 mL of THF was cooled in an ice-water bath and 12.2 grams (0.046 mole) of triphenylphosphine was added in one portion. Upon completion of addition 9 mL (0.046 mole) of diisopropyl azodicarboxylate was added dropwise during a five minute period. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature where it stirred during an 18 hour period. After this time the reaction mixture was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using methylene chloride as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 21 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.