Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[C:27]5[C:22](=[CH:23][CH:24]=[C:25]([NH:28][C:29]([NH:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])=S)[CH:26]=5)[N:21]=[CH:20][N:19]=4)=[CH:13][C:12]=3[CH3:37])=[CH:6][C:5]=12.[OH-].[Na+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>O1CCCC1>[N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[C:27]5[C:22](=[CH:23][CH:24]=[C:25]([NH:28][C:29]6[O:34][CH2:33][C:32]([CH3:36])([CH3:35])[N:31]=6)[CH:26]=5)[N:21]=[CH:20][N:19]=4)=[CH:13][C:12]=3[CH3:37])=[CH:6][C:5]=12
Reactant: Cc1cc(Nc2ncnc3ccc(NC(=S)NC(C)(C)CO)cc23)ccc1Oc1ccn2ncnc2c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Nc2ncnc3ccc(NC4=NC(C)(C)CO4)cc23)ccc1Oc1ccn2ncnc2c1

Procedure:
The synthesis of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine is described in WO 2007/059257. Generally, N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine may be prepared by coupling (E)-N′-(2-cyano-4-(3-(1-hydroxy-2-methylpropan-2-yl)thioureido)phenyl)-N,N-dimethylformimidamide with 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline in isopropyl acetate:acetic acid (65:35 v/v) at 45° C. to yield 1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)-3-(1-hydroxy-2-methylpropan-2-yl)thiourea. The 1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)-3-(1-hydroxy-2-methylpropan-2-yl)thiourea may then be agitated in tetrahydrofuran under basic conditions (2.5N NaOH), followed by the addition of p-toluenesulfonyl chloride. Water may then be charged to yield N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine as a mixture of polymorphs (generally a mixture containing one or more of Form C, Form G hemi-THF, Form G mono-THF, Form M or Form P). The final crystallizations or isolations will determine the polymorphic form, which are further detailed in the Examples section.
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.Cl[CH2:16][C:17](Cl)=[O:18]>C(Cl)(Cl)Cl>[CH3:6][C:2]1([CH3:7])[O:1][C:17](=[O:18])[CH2:16][O:4][C:3]1=[O:5]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC1(C)OC(=O)COC1=O
Reaction time: 1 h
Yield: 10.4 %

Procedure:
To a flask containing two liters of chloroform, 1 mole of 2-hydroxy-isobutyric acid (104.1 gms.) and 2.2 moles of triethylamine (224 gms.), cooled in an ice bath, was slowly added 1 mole of chloroacetyl chloride (127 gms.). Addition took one hour. The chloroform was evaporated to yield a reddish semi-solid which was triturated several times with acetone followed by decantation of the reddish acetone extract. The white solid residue was triethylamine hydrochloride. The acetone extracts were combined and concentrated under vacuum to a red oil which was distilled under vacuum. The fraction distilling at 103°-110°C./0.7-0.9 torr. was collected. This fraction solidified to a green semi-solid which was recrystallized from isopropyl alcohol and then sublimed at 75°C./0.1 torr. to yield 15 grams of white solid, m.p. 82°-83°C. This was dissolved in 3000 ml. of benzene at 10°C. and extracted successively with three 300 ml. portions of 0.01 N HCl solution saturated with sodium chloride in a separatory funnel, and the benzene layer quickly dried by filtration through a bed of anhydrous sodium sulfate into a flask containing anhydrous magnesium sulfate. After the removal of the magnesium sulfate by filtration and the benzene under vacuum, the solid 3,3-dimethyl-1,4-dioxane-2,5-dione was recrystallized from isopropyl alcohol and sublimed at 75°C/0.1 torr. to yield 13 grams of solid, m.p. 85°-86°C., % C found = 50.00 vs. 50.00 calculated, % H found = 5.52 vs. 5.60 calculated.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:10][S:11][CH2:12][C@H:13]([O:29][C:30](=[O:42])[NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:14][O:15][C:16](=[O:28])[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].CCN(C(C)C)C(C)C.[C:52](Cl)(=[O:68])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67]>C(Cl)Cl>[CH2:32]([NH:31][C:30]([O:29][C@H:13]([CH2:14][O:15][C:16](=[O:28])[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:12][S:11][CH2:10][C@H:2]([NH:1][C:52](=[O:68])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])[C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])=[O:42])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](N)C(=O)OC(C)(C)C)OC(=O)NCCCCCCCCCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCCCCC(=O)N[C@@H](CSC[C@@H](COC(=O)NCCCCCCCCCC)OC(=O)NCCCCCCCCCC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (R)-tert-butyl 2-amino-3-((R)-2,3-bis(decylcarbamoyloxy)propylthio)propanoate in dry DCM (0.1 M) at 0° C. was added DIEA (1.2 eq) and palmitoyl chloride (1.1 eq). The reaction was allowed to warm to room temperature then stirred for 16 hours. The crude reaction was then concentrated and purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient 0-60% EtOAc/Hex to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH2:29]([NH2:34])[CH2:30][CH2:31][CH2:32][CH3:33]>C(Cl)(Cl)Cl>[CH2:29]([NH:34][C:12]([C:9]1[C:8](=[O:15])[N:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]2=[N:11][CH:10]=1)=[O:14])[CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCN
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCNC(=O)c1cnc2cccc(C)n2c1=O
Reaction time: 0.08 h
Yield: 55.8 %

Procedure:
A mixture containing 8.16 g (0.04 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 6.2 ml (0.044 mol) of triethylamine in 240 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 4 ml (0.042 mol) of ethyl chloroformate in 20 ml of chloroform is dropped to the above mixture at -15° C. during 20 minutes. After stirring for 5 minutes, 3.835 g (0.044 mol) of n-pentylamine dissolved in 40 ml of chloroform are dropped to the above solution at -15° C. during 20 minutes. The reaction mixture is stirred below -10° C. for 1 hour and then let to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 100 ml of 5% sodium hydrogen carbonate solution each and then 3 times with 100 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to give 6.1 g (55.8%) of the named product as orange yellow crystals after recrystallization from ethanol, m.p.: 112°-116° C.
Reaction SMILES: [CH:1]1([C:7]2[NH:11][C:10](=[O:12])[C:9]3([CH2:17][CH2:16][N:15]([S:18](/[CH:21]=[CH:22]/[C:23]4[C:31]5[O:30][C:29](=[O:32])[NH:28][C:27]=5[CH:26]=[CH:25][CH:24]=4)(=[O:20])=[O:19])[CH2:14][CH2:13]3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.CN(C=O)C.[Pd]>[CH:1]1([C:7]2[NH:11][C:10](=[O:12])[C:9]3([CH2:17][CH2:16][N:15]([S:18]([CH2:21][CH2:22][C:23]4[C:31]5[O:30][C:29](=[O:32])[NH:28][C:27]=5[CH:26]=[CH:25][CH:24]=4)(=[O:20])=[O:19])[CH2:14][CH2:13]3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1NC(C2CCCCC2)=NC12CCN(S(=O)(=O)/C=C/c1cccc3[nH]c(=O)oc13)CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C1NC(C2CCCCC2)=NC12CCN(S(=O)(=O)CCc1cccc3[nH]c(=O)oc13)CC2
Yield: 82.8 %

Procedure:
10% Pd—C (28 mg) was added to a solution of 2-cyclohexyl-8-[(E)-2-(2-oxo-2,3-dihydro-benzoxazol-7-yl)-ethenesulfonyl]-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (56.6 mg, 0.123 mmol) in MeOH-DMF (4 ml, 1:1). The mixture was stirred at room temperature overnight in a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was then concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate, and the organic layer was then washed with water (×2), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, AcOEt-hexane) to give 2-cyclohexyl-8-[2-(2-oxo-2,3-dihydro-benzoxazol-7-yl)-ethanesulfonyl]-1,3,8-triaza-spiro[4.5]dec-1-en-4-one as a colorless foam (46.9 mg, 83%).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1.[N:30]1([C:36]2[CH:45]=[N:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]=2)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26][N:33]3[CH2:34][CH2:35][N:30]([C:36]4[CH:45]=[N:44][C:43]5[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=5)[N:37]=4)[CH2:31][CH2:32]3)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc2nc(N3CCNCC3)cnc2c1
Product: O=C(NCc1ccc(F)cc1)C1(CCCCN2CCN(c3cnc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluoro-benzylamide and 2-piperazin-1-yl-quinoxaline.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[C:10]1([CH2:16][CH2:17][CH2:18][CH2:19]O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([CH2:16][CH2:17][CH2:18][CH2:19][O:8][C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCCCCc1ccccc1
Reactant: O=C(O)CCCCCBr
Product: O=C(CCCCCBr)OCCCCc1ccccc1
Yield: 80 %

Procedure:
From 6-bromocaproic acid and 4-phenyl-1-butanol. Working up by means of distillation. Yield: 80%. Boiling point: 158° C. (0.008 mbar).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].[Cl:6][CH2:7][C:8]([NH:10][C:11]1[CH:12]=[N:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=1)=[O:9]>CO>[Cl:6][CH2:7][C:8]([NH:10][C:11]1[CH:12]=[N:13][C:14]([C:17](=[N:2][OH:3])[NH2:18])=[CH:15][CH:16]=1)=[O:9]
Reactant: N#Cc1ccc(NC(=O)CCl)cn1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: NC(=NO)c1ccc(NC(=O)CCl)cn1
Reaction time: 0.5 h

Procedure:
Hydroxylamine hydrochloride (0.16 g, 2.3 mmol) was added to a solution of potassium hydroxide (0.152 g, 2.3 mmol) in methanol and the mixture was stirred for 30 minutes and filtered. To the filtrate, compound of example 3 (0.3 g, 1.53 mmol) was added and reaction mixture was refluxed for 4 hours. After completion of reaction the mixture was cooled, concentrated and triturated with diethyl ether to obtain the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16](Br)[CH:17]=2)[N:12]=[C:11]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:23]=2)[C:10]=1[CH3:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:37]1[CH:42]=[CH:41][CH:40]=[C:39](OB(O)O)[CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.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>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:39]3[CH:38]=[N:37][CH:42]=[CH:41][CH:40]=3)[CH:17]=2)[N:12]=[C:11]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:23]=2)[C:10]=1[CH3:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)Oc1cccnc1
Reactant: Cc1c(COc2cccc(OCC3CCOCC3)c2)nc2ccc(Br)cc2c1OCc1ccccc1
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: C1COCCO1
Solvent: O
Product: Cc1c(COc2cccc(OCC3CCOCC3)c2)nc2ccc(-c3cccnc3)cc2c1OCc1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a solution of 4-(benzyloxy)-6-bromo-3-methyl-2-{[3-(tetrahydro-2H-pyran-4-ylmethoxy)phenoxy]methyl}quinoline (300 mg) in dioxane (10 mL) were added pyridin-3-yl boric acid (135 mg), tetrakis(triphenylphosphine)palladium(0) (65 mg), and a 1M aqueous sodium carbonate solution (1.60 mL), followed by stirring at 80° C. for 2 hours. The reaction mixture was allowed to cool to room temperature, and water (20 mL) was added thereto, followed by extraction with chloroform (50 mL). The organic layer was washed sequentially with a saturated aqueous sodium hydrogen carbonate solution and saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=15/85) to obtain 4-(benzyloxy)-3-methyl-6-(pyridin-3-yl)-2-{[3-(tetrahydro-2H-pyran-4-ylmethoxy)phenoxy]methyl}quinoline (265 mg).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[NH2:19][C:20]1[N:25]=[C:24](Cl)[N:23]=[C:22]([C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=2[Cl:34])[N:21]=1>O>[NH2:19][C:20]1[N:25]=[C:24]([N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4])[N:23]=[C:22]([C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=2[Cl:34])[N:21]=1
Reactant: Nc1nc(Cl)nc(-c2cc(Cl)ccc2Cl)n1
Reactant: OCCNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(-c2cc(Cl)ccc2Cl)nc(N(CCO)CCO)n1
Temperature: 25 °C
Yield: 96.1 %

Procedure:
To a mixture of 9.2 g of diethanolamine, 200 ml of N,N-dimethylformamide, and 15 g of anhydrous potassium carbonate was added 20 g of 2-amino-4-chloro-6-(2,5-dichlorophenyl)-1,3,5-triazine with stirring at room temperature and the mixture was further stirred at room temperature for 7 hours. This reaction mixture was diluted with 2 L (liters) of water with stirring and then stirred for 1 hour. The resulting crystals were collected by filtration, rinsed with water, and dried to obtain 24 g of white crystals. Those crystals were recrystallized from methanol, collected by filtration, and dried to give 21 g of the title compound as white crystals.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C(N(CC)C(C)C)(C)C.C([O:23][C:24](=O)[CH:25]=[C:26]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=1[F:37])[CH2:27]Br)C>C(#N)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([N:6]1[CH2:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=2[F:37])=[CH:25][C:24]1=[O:23])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CCOC(=O)C=C(CBr)Oc1cccc(Cl)c1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)[C@H](CC(C)C)N1CC(Oc2cccc(Cl)c2F)=CC1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 51.9 %

Procedure:
A mixture of (L)-leucine methyl ester hydrochloride (0.94 g, 5.17 mmol) in acetonitrile (11 mL) was treated with N,N-diisopropylethylamine (0.84 mL, 5.08 mmol). After addition was complete, the mixture was stirred at 60° C. for 1 h. At this time, the reaction was cooled to 25° C., treated with N,N-diisopropylethylamine (0.84 mL, 5.08 mmol) and acetonitrile (11 mL) and then heated to 80° C. Upon reaching 80° C., the reaction was treated with a solution of 4-bromo-3-(3-chloro-2-fluoro-phenoxy)-but-2-enoic acid ethyl ester (1.59 g, 4.71 mmol) in acetonitrile (11 mL). After the addition was complete the reaction mixture was heated to 100° C. and stirred overnight. At this time, the reaction mixture was cooled to 25° C. and concentrated in vacuo. The residue was diluted with dichloromethane (100 mL) and was washed with a 2N aqueous hydrochloric acid solution (1×100 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL), a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, rinsed with dichloromethane and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 15-50% ethyl acetate/hexanes) afforded (S)-2-[4-(3-chloro-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (0.87 g, 52%) as a red/orange oil: HR-ES-MS m/z calculated for C17H19NO4FCl [M+H]+ 356.1060, observed 356.1060; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.88 (d, J=6.6 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H), 1.36-1.54 (m, 1H), 1.62 (ddd, J=14.0, 9.6, 4.6 Hz, 1H), 1.81 (ddd, J=14.0, 11.4, 4.6 Hz, 1H), 3.66 (s, 3H), 4.22 (d, J=18.3 Hz, 1H), 4.28 (d, J=18.3 Hz, 1H), 4.74 (dd, J=11.4, 4.6 Hz, 1H), 5.07 (s, 1H), 7.33 (td, J=8.1, 1.4 Hz, 1H), 7.48-7.55 (m, 1H), 7.58 (ddd, J=8.1, 6.7, 1.4 Hz, 1H).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH3:20])[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:34][OH:35]>O1CCCC1>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH3:20])[N:16]=2)[CH2:11][C:12]([NH:34][OH:35])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Reactant: NO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.5 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)hexanoic acid (Preparation 45) (170 mg, 0.61 mmol) in anhydrous tetrahydrofuran (2 ml) was treated with 1,1′-carbonyldiimidazole (98 mg, 0.61 mmol) and the mixture stirred at room temperature under a nitrogen atmosphere for 20 minutes. Hydroxylamine hydrochloride (42 mg, 0.61 mmol) was then added and the mixture stirred for 18 hours. The solvent was removed under reduced pressure and the residue partitioned between hydrochloric acid (0.5M) and ethyl acetate. The layers were separated and the organic phase was washed with water, dried over anhydrous sodium sulphate, filtered and solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol (98:2) to afford the title compound as an oil (82 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([C:12]3[CH:40]=[CH:39][C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([CH2:29][CH2:30][CH2:31][C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])(C(O)=O)[C:23]([OH:25])=[O:24])=[CH:14][CH:13]=3)=[O:11])=[C:8]([C:41]3[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=3)[S:7][C:6]=2[CH:48]=1>CS(C)=O.O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([C:12]3[CH:40]=[CH:39][C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([CH2:29][CH2:30][CH2:31][C:32]([F:38])([F:37])[C:33]([F:34])([F:35])[F:36])[C:23]([OH:25])=[O:24])=[CH:14][CH:13]=3)=[O:11])=[C:8]([C:41]3[CH:42]=[CH:43][C:44]([OH:47])=[CH:45][CH:46]=3)[S:7][C:6]=2[CH:48]=1
Reactant: O=C(c1ccc(OCCCCCC(CCCC(F)(F)C(F)(F)F)(C(=O)O)C(=O)O)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Solvent: CS(C)=O
Solvent: O
Product: O=C(c1ccc(OCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Temperature: 120 °C
Reaction time: 3 h
Yield: 71.2 %

Procedure:
2-[5-[4-[(6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)carbonyl]-phenoxy]pentyl]-2-(4,4,5,5,5-pentafluoropentyl)malonic acid (1.1 g, 1.58 mmol) was dissolved in dimethyl sulfoxide (10 ml) and stirred for 3 hours at 120° C. The reaction mixture was cooled to room temperature, diluted with water, and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/1) to give 2-[5-[4-[(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)carbonyl]phenoxy]pentyl]-6,6,7,7,7-pentafluoroheptanoic acid (732 mg, Yield 71%) as a yellow solid.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][C:7](=[O:16])[NH:6][C:5]=2[N:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:24][CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>CN(C)C=O>[Si:27]([O:26][CH2:25][CH2:24][N:6]1[C:5]2[N:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8][C:7]1=[O:16])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: O=C1Cc2ccccc2-c2cccnc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCN1C(=O)Cc2ccccc2-c2cccnc21
Temperature: 40 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Heat a mixture 5,7-dihydropyrido[2,3-d][3]benzazepin-6-one (22.5 g, 106.9 mmol) and dimethylformamide (500 mL) to 100° C. for 5 minutes. Cool to 40° C., add cesium carbonate (104.3 g, 320.1 mmol) and (2-bromoethoxy)-tert-butyldimethylsilane (29.9 mL, 138.9 mmol) and stir at ambient temperature overnight. Heat to 60° C. for approximately 2 hours, and then cool to ambient temperature. Partition the residue between ethyl acetate (1 L) and water (3 L), back extract from aqueous layer with ethyl acetate (2×500 mL), wash combined organics with brine (2×500 mL). Dry combined organics over sodium sulfate and concentrate. Purify the residue by flash chromatography, eluting with ethyl acetate:hexane (0:100 to 100:0) to give the title compound as an oil (39.4 g, 106.9 mmol, 89%). MS (m/z): 369 (M+1).
Reaction SMILES: OS(O)(=O)=O.[Cl:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1.[N+:17]([O-])([O-:19])=[O:18].[K+]>>[Cl:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Clc1ccc2ccccc2n1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cccc2ccc(Cl)nc12
Temperature: 25 °C
Yield: 35.2 %

Procedure:
Conc. H2SO4 was added slowly to 2-chloroquinoline (1.0 g, 6.13 mmol), followed by portionwise addition of potassium nitrate (800 mg, 7.97 mmol) at 0° C. The mixture was allowed to warm to room temperature overnight. After completion of the reaction (monitored by TLC and HPLCMS), the solution was poured slowly over ice, and the precipitate was extracted with EtOAc. The organic phase was washed with brine and concentrated in vacuo. The crude residue was purified by column chromatography with n-hexane/EtOAC (17:3) as the eluent to give the title compound (450 mg, 38%).