Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][C:33]1[CH:34]=[C:35]([CH:40]=[CH:41][C:42]=1[N+:43]([O-:45])=[O:44])[C:36]([O:38][CH3:39])=[O:37].[CH3:46][C:47](=[CH2:50])[CH2:48]O.Cl>O1CCCC1.O>[CH3:48][C:47](=[CH2:46])[CH2:50][O:32][C:33]1[CH:34]=[C:35]([CH:40]=[CH:41][C:42]=1[N+:43]([O-:45])=[O:44])[C:36]([O:38][CH3:39])=[O:37]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Reactant: C=C(C)CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)COc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
Triphenyl phosphine (7.87 g, 30 mmol) was dissolved in 80 mL of tetrahydrofuran followed by the addition of diethyl azodicarboxylate (5.23 g, 30 mmol) in a dry ice bath. The reaction mixture was stirred 30 minutes, added dropwise with a solution of methyl 3-hydroxy-4-nitro-benzoate 1b (2.96 g, 15 mmol) in tetrahydrofuran, and stirred 10 minutes followed by the addition of 2-methyl-allyl alcohol (1.41 g, 19.50 mmol), then stirred for another 1 hour. The resulting mixture was heated to room temperature and stirred for 12 hours. The resulting mixture was added with 10 mL of water, added dropwise with 1 M hydrochloric acid to adjust pH to 2 to 3 and extracted with ethyl acetate (50 mL×3). The combined organic phase was added dropwise with 1 M sodium hydroxide solution to adjust pH to 9 to 10, extracted with ethyl acetate (50 mL×2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound methyl 3-(2-methylallyloxy)-4-nitro-benzoate 4a (3 g, yield: 79.6%) as a light yellow solid.
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[C:5]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1.[C:19]([O:23][C:24]([NH:26][C@H:27]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:28](O)=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20].ON1C2C=CC=CC=2N=N1.O.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>C(Cl)Cl>[Br:3][C:4]1[C:5]([N:13]2[CH2:18][CH2:17][N:16]([C:28](=[O:29])[C@H:27]([NH:26][C:24](=[O:25])[O:23][C:19]([CH3:20])([CH3:21])[CH3:22])[CH2:31][C:32]3[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=3)[CH2:15][CH2:14]2)=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: Brc1cnc2[nH]ccc2c1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2c(Br)cnc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.4 %

Procedure:
5-Bromo-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine dihydrochloride (0.20 g, 0.56 mmol) and (R)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (0.677 g, 2.25 mmol) were placed in DCM (5 mL) at room temperature. 1-Hydroxybenzotriazole (“HOBT”)—H2O (0.121 g, 0.79 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (“EDCI”; 0.14 g, 0.73 mmol), and triethylamine (0.39 mL, 2.82 mmol) were then added, and the reaction was stirred at room temperature for 18 hours. The reaction was then quenched with saturated Na2CO3 and extracted with DCM. The combined organic fractions were dried, filtered, and concentrated to give a crude residue. The crude residue was purified by column chromatography (500:7 DCM:MeOH) to give (R)-tert-butyl 1-(4-(5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-3-(4-chlorophenyl)-1-oxopropan-2-ylcarbamate (0.20 g, 62.9% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](=[O:11])(=[O:10])[NH2:9].Br[CH2:13][C:14]([NH:16][CH3:17])=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+].C(=O)(O)[O-].[K+]>>[S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][CH2:13][C:14]([NH:16][CH3:17])=[O:15])(=[O:11])(=[O:10])[NH2:9]
Reactant: CNC(=O)CBr
Reactant: NS(=O)(=O)c1ccccc1O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)COc1ccccc1S(N)(=O)=O

Procedure:
2-(2-Sulfamoylphenoxy)-N-methylacetamide can be prepared according to the method of Scheme XXXIX. Bromoacetyl bromide can be reacted methylamine hydrochloride in the presence of a base, such as sodium hydroxide to afford 2-bromo-N-methylacetamide. The phenoxy group of 1-(hydroxy)-2-sulfamoylbenzene can be alkylated with 2-bromo-N-methylacetamide in the presence of a base, such as cesium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and the like, to afford 2-(2-sulfamoylphenoxy)-N-methylacetamide.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.C1C2C(COC([NH:29][C@@H:30]([CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][C:46]([N:49]=[N+:50]=[N-:51])=[CH:45][CH:44]=3)=[O:40])[C:31]([OH:33])=[O:32])=O)C3C(=CC=CC=3)C=2C=CC=1>CN(C=O)C>[NH2:29][C@@H:30]([CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:39]([O:41][CH2:42][C:43]1[CH:44]=[CH:45][C:46]([N:49]=[N+:50]=[N-:51])=[CH:47][CH:48]=1)=[O:40])[C:31]([OH:33])=[O:32]
Reactant: [N-]=[N+]=Nc1ccc(COC(=O)NCCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=Nc1ccc(COC(=O)NCCCC[C@H](N)C(=O)O)cc1
Reaction time: 0.33 h
Yield: 80.6 %

Procedure:
DBU (0.064 mL, 0.425 mmol) was added to a solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-6-((((4-azidobenzyl)oxy)carbonyl)amino)hexanoic acid (Compound SP661) (210 mg, 0.386 mmol) in DMF (0.7 mL) at room temperature under a nitrogen atmosphere. The resulting reaction mixture was stirred at the same temperature for 20 minutes and then purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (S)-2-amino-6-((((4-azidobenzyl)oxy)carbonyl)amino)hexanoic acid (Lys(Acbz)) (Compound tk34) (100 mg, 81%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C@@H:15]3[CH2:19][CH2:18][NH:17][C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.O[C@H]1CCNC1=O.Cl[CH2:31][C:32]1[NH:33][C:34](=[O:42])[C:35]2[CH2:41][O:40][CH2:39][CH2:38][C:36]=2[N:37]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C@@H:15]3[CH2:19][CH2:18][N:17]([CH2:31][C:32]4[NH:33][C:34](=[O:42])[C:35]5[CH2:41][O:40][CH2:39][CH2:38][C:36]=5[N:37]=4)[C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:21][CH:22]=1
Reactant: COc1ccc(C(=O)C2CCN([C@@H]3CCNC3=O)CC2)cc1
Reactant: O=c1[nH]c(CCl)nc2c1COCC2
Agent: O=C1NCC[C@@H]1O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C2CCN([C@@H]3CCN(Cc4nc5c(c(=O)[nH]4)COCC5)C3=O)CC2)cc1
Temperature: 0 °C
Yield: 26 %

Procedure:
To a solution of (R)-3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-pyrrolidin-2-one (0.165 mmol, 50 mg), which was prepared in a similar manner as (R)-3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-pyrrolidin-2-one from (S)-3-hydroxypyrrolidin-2-one and 2-chloromethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (0.165 mmol, 33.2 mg) in THF (5 mL) was added 1 M solution of potassium hexamethyldisilylamide in THF (0.331 mmol, 0.331 mL) at −78° C. for 2 hours. The reaction was allowed to warm to 0° C. for 16 hours and evaporated under vacuum. The remaining residue was purified by flash column chromatography (silica) eluting over a gradient of 0-50% MeOH/ethyl acetate provided the title compound as an off-white solid (20 mg, 25.9% yield). HRMS calculated for C25H30N4O5 466.5417. found (ESI, [M+H]′) 467.2296. 1H NMR (400 MHz, MeOD) 8 ppm 1.69-1.91 (m, 4H) 2.10-2.33 (m, 2H) 2.49-2.59 (m, 1H) 2.59-2.67 (m, 2H) 2.76-2.89 (m, 1H) 2.91-3.01 (m, 1H) 3.11-3.22 (m, 1H) 3.32-3.44 (m, 2H) 3.46-3.58 (m, 2H) 3.59-3.71 (t, J=8.78 Hz, 1H) 3.88-3.96 (m, 2H) 4.04-4.14 (d, J=15.56 Hz, 2H) 4.36-4.42 (m, 2H) 4.44-4.51 (m, 2H) 6.97 (d, J=9.03 Hz, 2H) 7.92 (d, J=9.03 Hz, 2H), analytical RP-HPLC retention time=4.02 min.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:11][O:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]2[N:22]=[C:23]([NH2:25])[CH:24]=[C:18]2[CH2:17]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:8][C:6]1[CH:7]=[C:2]([NH:25][C:23]2[CH:24]=[C:18]3[CH2:17][N:16]([CH2:15][CH2:14][CH2:13][O:12][CH3:11])[CH2:21][CH2:20][N:19]3[N:22]=2)[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: COCCCN1CCn2nc(N)cc2C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COCCCN1CCn2nc(Nc3cc(Br)cn(C)c3=O)cc2C1
Temperature: 100 °C
Yield: 42.1 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 3,5-dibromo-1-methylpyridin-2(1H)-one (320 mg, 1.2 mmol), 309b (250 mg, 1.2 mmol), tris(dibenzylideneacetone)dipalladium(0) (55 mg, 0.060 mmol), xantphos (70 mg, 0.12 mmol), cesium carbonate (782 mg, 2.4 mmol), and 1,4-dioxane (20 mL). The system was subjected to three cycles of vacuum/argon flush and heated at 100° C. for 5 h. It was then cooled to room temperature and filtered. The solid was washed with dichloromethane (2×10 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80:1 to 30:1) to afford 309c (200 mg, 42%) as yellow solid. MS-ESI: [M+H]+ 396.2
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH3:19][O:20][C:21]([C:23]1[C:24]([O:48][CH3:49])=[C:25]2[C:30](=[C:31]([O:37][Si](C(C)C)(C(C)C)C(C)C)[C:32]=1[C:33]([O:35][CH3:36])=[O:34])[N:29]=[CH:28][CH:27]=[CH:26]2)=[O:22].[C:50]1([C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[N+]=[N-])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>C1COCC1>[CH3:19][O:20][C:21]([C:23]1[C:24]([O:48][CH3:49])=[C:25]2[C:30](=[C:31]([O:37][CH:56]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[C:32]=1[C:33]([O:35][CH3:36])=[O:34])[N:29]=[CH:28][CH:27]=[CH:26]2)=[O:22]
Reactant: COC(=O)c1c(C(=O)OC)c(O[Si](C(C)C)(C(C)C)C(C)C)c2ncccc2c1OC
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1c(C(=O)OC)c(OC(c2ccccc2)c2ccccc2)c2ncccc2c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A 1M solution of TBAF in THF (4 ml) was added to 5-methoxy-8-triisopropylsilanyloxy-quinoline-6,7-dicarboxylic acid dimethyl ester (0.85 g, 1.9 mmol) in 20 ml dry THF. The reaction was stirred at rt for 1 h, at which time the reaction mixture was concentrated and the residue dissolved in 100 mL diethyl ether and washed with 25 mL 1N HCl, followed by 25 mL of saturated aq. NaCl. The organic layer was concentrated and the residue was dissolved in 40 mL dichloroethane. Diphenyldiazomethane (0.7 g, 3.8 mmol) was added and the reaction temperature was raised to 70° C. for 24 h. The reaction mixture was concentrated and the residue chromatographed on silica gel (1/1 hexanes/EtOAc) to give 8-benzhydryloxy-5-methoxy-quinoline-6,7-dicarboxylic acid dimethyl ester (0.8 g, 61% yield overall). 1H NMR (CDCl3) δ 8.85 (d, 1H), 8.45 (d, 1H), 7.45 (dd, 1H), 3.98 (s, 3H), 3.85 (s, 3H), 3.74 (s, 3H); MS: 480 (M+Na).
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=1[O:12][CH3:13])=[O:3].[C:14]([O:19][CH2:20]C)(=[O:18])[C:15]([O-])=[O:16].C[O-].[Na+:24].[Na].C(OC(C)C)(C)C>CO>[Na+:24].[CH3:13][O:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([O:10][CH3:11])[C:4]=1[C:2]([O-:3])=[CH:1][C:15](=[O:16])[C:14]([O:19][CH3:20])=[O:18]
Reactant: COc1cccc(OC)c1C(C)=O
Reactant: CCOC(=O)C(=O)[O-]
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(C)OC(C)C
Solvent: CO
Product: COC(=O)C(=O)C=C([O-])c1c(OC)cccc1OC
Reaction time: 8 h

Procedure:
A solution of 100 g of 2,6-dimethoxyacetophenone and 7.5 ml of ethyl oxalate in 520 ml of anhydrous MeOH is added slowly to a solution of sodium methylate prepared from 12.7 g of sodium and 285 ml of anhydrous MeOH. The reaction mixture is heated to reflux for 7 hours and left overnight at RT. It is poured into 2 liters of isopropyl ether and left stirring for 15 minutes. The expected product is obtained by filtration, washing with isopropyl ether and drying under vacuum, m=120 g, m.p.=178° C.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:16]([C:24]3([CH:27]([OH:29])[CH3:28])[CH2:26][CH2:25]3)[O:15][N:14]=2)=[CH:9][CH:8]=1)(C)(C)C.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1>[OH:29][CH:27]([C:24]1([C:16]2[O:15][N:14]=[C:13]([C:10]3[CH:9]=[CH:8][C:7]([OH:6])=[CH:12][CH:11]=3)[C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:26][CH2:25]1)[CH3:28]
Reactant: CC(O)C1(c2onc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)c2-c2ccccc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(O)C1(c2onc(-c3ccc(O)cc3)c2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (±)-1-(1-{3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-4-phenyl-isoxazol-5-yl}-cyclopropy)-ethanol, which may be produced as in Example 178A (2.2 g) in 60 mL of anhydrous THF is added tetrabutylammonium fluoride hydrate (2.6 g.) The reaction mixture is stirred at room temperature for 4 hrs. Saturated ammonium chloride (50 mL) is added to the reaction mixture, followed with 300 mL of ethyl acetate. The aqueous layer are separated and then the organic layer is washed with additional saturated ammonium chloride (2×50 mL), followed with brine (50 mL). The organic layer is dried (sodium sulfate), filtered, and the filtrate is evaporated to give a white solid, which is purified by flash chromatography (silica gel, 40% ethyl acetate in hexane) to afford a white solid as (±)-4-{5-{1-(1-hydroxy-ethyl)-cyclopropyl]-4-phenyl-isoxazol-3-yl}-phenol.
Reaction SMILES: CCCCCCCCCCCCCCCCCC[N+](C)(C)C.[Cl-].CCCCCCCCCCCCCCCCCCN(CCOCCO)CCOCCO.[C:55]([O:74]CCCC)(=[O:73])[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72].C(OCCCC)(=O)CCCCCCCCCCC.C(O)(=O)CCCCCCCCCCC/C=C\CCCCCCCC>CCCCCCCCCCCC[N+](C)(C)C.[Cl-]>[C:55]([OH:74])(=[O:73])[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62]/[CH:63]=[CH:64]\[CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCCCC
Agent: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)O
Agent: CCCCCCCCCCCC(=O)OCCCC
Agent: CCCCCCCCCCCCCCCCCCN(CCOCCO)CCOCCO
Product: CCCCCCCC/C=C\CCCCCCCC(=O)O

Procedure:
Examples of lubricating agents which can be used in the present invention are commercially available under the trade names of NAA-102, NAA-415, NAA-312, NAA-160, NAA-180, NAA-174, NAA-175, NAA-222, NAA-34, NAA-35, NAA-171, NAA-122, NAA-142, NAA-160, NAA-173K, Castor oil-cured fatty acid, NAA-42, NAA-44, Cation SA, Cation MA, Cation AB, Cation BB, Nymeen L-201, Nymeen L-202, Nymeen S-202, Nonion E-208, Nonion P-208, Nonion S-207, Nonion K-204, Nonion NS-202, Nonion NS-210, Nonion HS-206, Nonion L-2, Nonion S-2, Nonion S-4, Nonion O-2, Nonion LP-20R, Nonion PP-40R, Nonion SP-60R, Nonion OP-80R, Nonion OP-85R, Nonion LT-221, Nonion ST-221, Nonion OT-221, Monoguri MB, Nonion DS-60, Anon BF, Anon LG, Butyl stearate, butyl laurate, and erucic acid (produced by Nippon Oils and Fats Co.); Oleic acid produced by Kanto Chemical Co., Ltd.; FAL-205, FAL-123 produced by Takemoto Yushi Co., Ltd.; Enujerubu LO, Enujerubu IPM, and Sansosyzer E4030 (produced by Shin Nihon Rika Co., Ltd.); TA-3, KF-96, KF-96L, KF-96H, KF-410, KF-420 KF-965, KF-54, KF-50, KF-56, KF-907, KF-851, X-22-819, X-22-822, KF-905, KF-700,-KF-393, KF-857, KF-860 , KF-865, X-22-980, KF-101, KF-102, KF-103, X-22-3710, X-22-3715, KF-910, and KF-3935 (produced by Shin-Etsu Chemical Co., Ltd.); Armide P, Armide C, and Armoslip CP (produced by Lion Ahmer Co., Ltd.); Duomin TDO produced by Lion Fat and Oil Co., Ltd.; BA-41G produced by Nisshin Oil Mill Ltd.; Profan 2012E, Newpole PE61, Ionet MS-400, Ionet MO-200, Ionet DL-200, Ionet DS-300, Ionet DS-300, Ionet DS-1000, and Ionet DO-200 (produced by Sanyo Kasei Co., Ltd.).
Reaction SMILES: [F:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:25]([NH2:27])[CH3:26])[C:8]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:15][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.Cl[C:29]1[C:30]2[N:38]=[CH:37][CH:36]=[CH:35][C:31]=2[N:32]=[CH:33][N:34]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[F:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:25]([NH:27][C:29]3[C:30]4[N:38]=[CH:37][CH:36]=[CH:35][C:31]=4[N:32]=[CH:33][N:34]=3)[CH3:26])[C:8]([N:13]3[CH2:14][CH2:15][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:17][CH2:18]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(F)ccc2cc([C@H](C)N)c(N3CCN(c4ccccn4)CC3)nc12
Reactant: Clc1ncnc2cccnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1c(F)ccc2cc([C@H](C)Nc3ncnc4cccnc34)c(N3CCN(c4ccccn4)CC3)nc12
Yield: 58.1 %

Procedure:
Following the procedure described for Intermediate 13, Intermediate 14 (530 mg, 1.1 mmol) and TFA (3 mL) in DCM (6 mL) afforded (S)-1-{7-fluoro-8-methyl-2-[4-(pyridin-2-yl)piperazin-1-yl]quinolin-3-yl}ethanamine as a white foam, which was used in the next step without any further purification. Following the procedure described for Example 5, (S)-1-{7-fluoro-8-methyl-2-[4-(pyridin-2-yl)piperazin-1-yl]quinolin-3-yl}ethanamine (60 mg, 0.16 mmol), 4-chloropyrido[3,2-d]pyrimidine (33 mg, 0.19 mmol) and DIPEA (0.14 mL, 0.8 mmol) in NMP (1.2 mL) afforded the title compound (46 mg, 58%) as a beige solid. δH (DMSO-d6) 8.94-8.89 (2H, m), 8.56 (1H, s), 8.52 (1H, s), 8.20-8.16 (2H, m), 7.91 (1H, dd, J 8.5, 4.3 Hz), 7.74 (1H, dd, J 8.9, 6.3 Hz), 7.65-7.55 (1H, m), 7.32 (1H, t, J 9.1 Hz), 6.96 (1H, d, J 8.6 Hz), 6.71 (1H, dd, J 7.1, 4.9 Hz), 5.95 (1H, m), 3.87-3.69 (6H, m), 3.33-3.23 (2H, m), 2.58 (3H, s), 1.68 (3H, d, J 6.7 Hz). LCMS (ES+) 495 (M+H)+, RT 3.09 minutes (Method 4).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH:11]=[CH:10][N:9]=1.C(N(CC)CC)C.O1CCCC1>O>[C:1]([NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=2)[CH:11]=[CH:10][N:9]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Cl
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Reaction time: 1 h

Procedure:
Butyroyl chloride (0.93 ml) was added dropwise to a stirred solution of 2-amino-4-(4-nitrophenoxy)pyridine (1.0 g), triethylamine (1.8 ml) and tetrahydrofuran (20 ml) at room temperature. After stirring for 1 hour, water was added, extraction was performed with ethyl acetate, the extract was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethylacetate=2:1) to obtain 0.6 g of the target substance as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])=O)=[CH:4][CH:3]=1.CC[O-].[Na+].[Na]>C(O)C>[F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:9](=[O:10])[CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(CC(=O)c1ccc(F)cc1)Nc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: O=c1cc(-c2ccc(F)cc2)c2ccccc2[nH]1
Yield: 84.1 %

Procedure:
To a refluxed solution of 40 g of 2-(4-fluorobenzoyl)acetanilide in 300 ml of ethanol, a sodium ethylate solution, prepared from 9.13 g of sodium and 150 ml of ethanol, is added dropwise over a period of 2 hours. The reaction mixture is refluxed for 20 minutes, allowed to cool and poured onto ice-water. The precipitate is collected, dried and recrystallized from chloroform - diethyl ether to give 31.3 g of the title compound, m.p. 247°-248° C.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([P:12]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:7]=1)(=O)C.[OH-].[Na+].C(O)C.C(OCC)(=O)C>O1CCCC1.O>[CH2:18]([O:17][P:12]([C:9]1[CH:8]=[CH:7][C:6]([CH2:5][OH:4])=[CH:11][CH:10]=1)([O:14][CH2:15][CH3:16])=[O:13])[CH3:19]
Reactant: CCOP(=O)(OCC)c1ccc(COC(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a stirred solution of 3.0 grams (0.01 mole) of 4-(diethylphosphono)phenylmethyl acetate in 10 mL of tetrahydrofuran was added a solution of 0.4 gram (0.01 mole) of sodium hydroxide in 1 mL of water. Upon completion of the addition, the reaction mixture was stirred at ambient temperature for one hour. After this time 5 mL of ethanol was added, and the reaction mixture was warmed to reflux, where it stirred for one hour. The reaction mixture was poured into a stirred mixture of water and ethyl acetate. The organic layer was separated and dried with magnesium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure, yielding 2.1 grams of 4-(diethylphosphono)phenylmethanol. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(C(C)C)CC)(C)C.[CH3:24][N:25]1[CH:29]=[C:28]([C:30]2[N:35]=[CH:34][C:33]([C:36](Cl)=[O:37])=[CH:32][CH:31]=2)[CH:27]=[N:26]1>ClCCl>[CH3:24][N:25]1[CH:29]=[C:28]([C:30]2[N:35]=[CH:34][C:33]([C:36]([N:7]3[C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=4[CH2:10][N:4]4[CH:3]=[CH:2][CH:1]=[C:5]4[CH2:6]3)=[O:37])=[CH:32][CH:31]=2)[CH:27]=[N:26]1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: Cn1cc(-c2ccc(C(=O)Cl)cn2)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1cc(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cn2)cn1
Reaction time: 18 h

Procedure:
A solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.37 g) and diisopropylethylamine (0.61 g) in dichloromethane (25 ml) was cooled to 0° C. and a solution of 6-(1-methyl-1H-pyrazol-4-yl)pyridine-3-carbonyl chloride in dichloromethane (25 ml) was added portionwise. After 18 hours at room temperature, the reaction mixture was washed with water and a saturated aqueous sodium bicarbonate solution. The dichloromethane solution was dried over anhydrous sodium sulfate and filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (0.31 g), m.p. 173-175° C.; MS, m/z: 370.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[F:1])[C:6]#[N:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C#N)ccc1F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(F)c(CBr)c1
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
To a solution of 4-fluoro-3-methylbenzonitrile (15.0 g, 111 mmol), in CCl4 (600 mL) was added N-bromosuccinimide (23.7 g, 133 mmol), and benzoyl peroxide (5.38 g, 22.2 mol). The mixture was irradiated with a sunlamp (250 W) to create a gentle reflux. After 0.5 hours of exposure the reaction was complete by TLC. The reaction mixture was cooled and filtered through celite. The filtrate was condensed in vacou to yield brown oil. The crude residue was purified via silica gel column chromatography (hexanes/ethyl acetate) to yield 17.7 g of the desired product.