Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:7][CH2:6][CH2:5][O:4][C:3]2[C:8]([CH2:12][NH:13][CH3:14])=[CH:9][CH:10]=[CH:11][C:2]1=2.Cl.[O:16]=[C:17]1[NH:26][C:25]2[N:24]=[CH:23][C:22](/[CH:27]=[CH:28]/[C:29]([OH:31])=O)=[CH:21][C:20]=2[CH2:19][CH2:18]1>>[O:1]1[CH2:7][CH2:6][CH2:5][O:4][C:3]2[C:8]([CH2:12][N:13]([CH3:14])[C:29](=[O:31])[CH:28]=[CH:27][C:22]3[CH:23]=[N:24][C:25]4[NH:26][C:17](=[O:16])[CH2:18][CH2:19][C:20]=4[CH:21]=3)=[CH:9][CH:10]=[CH:11][C:2]1=2
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CNCc1cccc2c1OCCCO2
Agent: Cl
Product: CN(Cc1cccc2c1OCCCO2)C(=O)C=Cc1cnc2c(c1)CCC(=O)N2
Yield: 78.9 %

Procedure:
According to the procedure of Example 35g (3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-ylmethyl)-methyl-amine (239 mg, 1.24 mmol) and (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)acrylic acid hydrochloride (318 mg, 1.25 mmol), were coupled to give crude product. Purification by column chromatography (silica gel, 5% MeOH/CH2Cl2) gave the title compound (385 mg, 79%) as a yellow solid and a mixture of amide rotomers: 1H NMR (400 MHz, DMSO-d6) δ 10.66-10.63 (m, 1H), 8.36-8.32 (m, 1H), 8.07-8.03 (m, 1H), 7.51-7.46 (m, 1H), 7.30-721 (m, 1H), 6.93-6.88 (m, 2H), 6.78-6.76 (m, 1H), 4.76-4.59 (m, 2H), 4.13-4.06 (m, 4H), 3.11-2.84 (m, 5H), 2.54-2.52 (m, 2H), 2.11-2.07 (m, 2H); ESI MS m/e 394 [C22H23N3O4+H]+.
Reaction SMILES: [F:1][C:2]1([F:15])[O:7][C:6]2[CH:8]=[CH:9][C:10]([NH2:12])=[CH:11][C:5]=2[O:4][C:3]1([F:14])[F:13].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]#[CH:24].C1(C)C=CC=CC=1>C(#N)C>[CH2:24]([NH:12][C:10]1[CH:9]=[CH:8][C:6]2[O:7][C:2]([F:1])([F:15])[C:3]([F:13])([F:14])[O:4][C:5]=2[CH:11]=1)[C:23]#[CH:22]
Reactant: Nc1ccc2c(c1)OC(F)(F)C(F)(F)O2
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: C#CCNc1ccc2c(c1)OC(F)(F)C(F)(F)O2
Temperature: 67.5 °C
Reaction time: 24 h

Procedure:
Another method to prepare the titled compound is as follows. 2,2,3,3-Tetrafluoro-6-aminobenzodioxane (50.2 g, 225 mmol) and potassium carbonate (43.54 g, 315 mmol) were suspended into acetonitrile (250 mL), stirred in a 1-liter three-necked flask equipped with an overhead mechanical stirrer, and treated with ˜80% propargyl bromide in toluene (33.5 g, ˜225 mmol). The mixture was slowly heated to 65-70° C. over about three hours. Stirring was continued at that temperature for 24 hours, at which time the heat was turned off and the mixture was permitted to cool to room temperature. The mixture was filtered through a glass fritted funnel, and the solids were rinsed with acetonitrile (300 mL). The filtrate was concentrated, reconcentrated thrice from hexanes, and chromatographed on silica (0 to 1 to 2 to 4% EtOAc/hexanes) to give the titled compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)=[C:6]([OH:8])[CH:7]=1.O=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]3[CH:13]=[CH:12][CH:11]=[C:10]3[C:15]3([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[O:8][C:6]=2[CH:7]=1
Reactant: Cc1ccc(-n2cccc2)c(O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)OC1(CCN(C(=O)OC(C)(C)C)CC1)c1cccn1-2
Yield: 59.6 %

Procedure:
To 5-methyl-2-pyrrol-1-yl-phenol (6.0 g, 33.6 mmol) in dichloromethane (75 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate (6.61 g, 33.6 mmol) then trifluoroacetic acid (3.1 mL, 40.3 mmol) and the mixture was stirred at room temperature for 5.5 hours. The solvent was evaporated and the crude residue was purified by column chromatography utilizing a gradient of 0-100% dichloromethane in hexanes to yield tert-butyl 7′-methylspiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (7.1 g, 59%). 1H NMR (400 MHz, CDCl3) δ 7.22 (d, J=8.1 Hz, 1H), 7.12-7.09 (m, 1H), 6.88 (s, 1H), 6.82 (d, J=8.0 Hz, 1H), 6.29 (t, J=3.2 Hz, 1H), 6.00-5.98 (m, 1H), 5.30 (s, 1H), 3.97 (s, 2H), 3.26 (t, J=12.2 Hz, 2H), 2.32 (s, 3H), 2.09-2.01 (m, 2H), 1.87 (dt, J=13.3, 4.9 Hz, 2H), 1.48 (s, 9H). ESI-MS m/z calc. 354.4, found 355.5 (M+1)+; Retention time 2.28 minutes (3 min run).
Reaction SMILES: ClC1[CH:10]=[C:9]([NH:11][C:12]2C=CC(C(N3CCOCC3)=O)=C[CH:13]=2)[C:5](C(O)=O)=CN=1.[NH4+].[OH-].O1[CH2:33][CH2:32]OCC1.[CH3:34]N(C=O)C>>[CH3:13][CH2:12][N:11]([CH:32]([CH3:33])[CH3:34])[CH:9]([CH3:10])[CH3:5]
Reactant: C1COCCO1
Reactant: O=C(O)c1cnc(Cl)cc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: CN(C)C=O
Agent: [NH4+]
Agent: [OH-]
Product: CCN(C(C)C)C(C)C

Procedure:
A mixture of 6-chloro-4-(4-(morpholine-4-carbonyl)phenylamino)nicotinic acid (280 mg, 0.774 mmol) in DMF (10 mL) was treated with NH4OH 0.5 M solution in dioxane (7.74 mL, 3.87 mmol) and DIEA (0.676 mL, 3.87 mmol) to give a cloudy suspension. Then added HATU (589 mg, 1.548 mmol) and stirred at rt for 24 hrs. Diluted with water and extracted into ethyl acetate and washed with 10% LiCl and concentrated to give 230 mg of 6-chloro-4-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide as a white solid. LCMS: (M+H)+=361.03, 363.02 (Cl pattern).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:15]([O:17]CC)=[O:16])=[C:8]3[S:14][CH2:13][CH2:12][N:9]32)=[CH:4][C:3]=1[F:21].[OH-].[Na+].O.C(O)C>C(O)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:15]([OH:17])=[O:16])=[C:8]3[S:14][CH2:13][CH2:12][N:9]32)=[CH:4][C:3]=1[F:21]
Reactant: CCOC(=O)c1c2n(c3cc(Br)c(F)cc3c1=O)CCS2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)c1c2n(c3cc(Br)c(F)cc3c1=O)CCS2
Yield: 93 %

Procedure:
Then 1.0 gram of the fractioned ethyl 8-bromo-7-fluoro-5-oxo-1,2-dihydro-5H-thiazolo(3,2-a)-quinoline-4-carboxylate was suspended in a solution of 2.0 grams of sodium hydroxide (0.05 mmol), 50 ml of water and 20 ml of ethanol, the mixture was heated to reflux for four hours, the transparent solution was acidified with acetic acid after being cooled, crystals separated out were collected by filtration, washed with water, and dried. Thus, 860 mg (93.5 percent) of the title compound was obtained. Colorless powdery crystals were then recrystallized from dimethyl formamide. Melting point was 228° to 290° C. (decomposition).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:17]([O:19]CC)=[O:18])=[N:4][O:5][C:6]=1[C:7]1[CH2:16][CH2:15][C:10]2([CH2:14][O:13][CH2:12][CH2:11]2)[CH2:9][CH:8]=1.C1COCC1.[OH-].[Na+].Cl>CO.CCOC(C)=O>[CH3:1][C:2]1[C:3]([C:17]([OH:19])=[O:18])=[N:4][O:5][C:6]=1[C:7]1[CH2:16][CH2:15][C:10]2([CH2:14][O:13][CH2:12][CH2:11]2)[CH2:9][CH:8]=1
Reactant: CCOC(=O)c1noc(C2=CCC3(CCOC3)CC2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)noc1C1=CCC2(CCOC2)CC1
Temperature: 25 °C

Procedure:
[Ethyl 4-methyl-5-(2-oxaspiro[4.5]dec-7-en-8-yl)isoxazole-3-carboxylate] (170 mg, 0.584 mmol) in MeOH (3.60 mL) and THF (6 mL) was treated at room temperature with 2M NaOH (aq) (0.584 mL, 1.167 mmol). The resulting mixture was stirred at room temperature and treated with 2M HCl (aq) (0.2 mL) and EtOAc. The combined organic layers were dried over MgSO4 and filtered and the solvent was removed under reduced pressure to afford the title compound;
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:5]([F:14])=[CH:4][C:3]=1[N:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18](=[O:23])[C:17]([C:24](O)=[O:25])=[N:16]1.C1C=C[C:30]2[N:35]([OH:36])N=NC=2C=1.[CH2:37](N(CC)CC)C.CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[C:5]([F:14])=[CH:4][C:3]=1[N:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18](=[O:23])[C:17]([C:24]([N:35]([O:36][CH3:37])[CH3:30])=[O:25])=[N:16]1
Reactant: COc1cn(-c2cc(F)c(N3CCOCC3)cc2F)nc(C(=O)O)c1=O
Reactant: On1nnc2ccccc21
Reactant: CCN(CC)CC
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cn(-c2cc(F)c(N3CCOCC3)cc2F)nc(C(=O)N(C)OC)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
A mixture of 1-(2,5-difluoro-4-morpholin-4-ylphenyl)-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (2.5 g, 6.8 mmol), N,0-dimethylhydroxylamine hydrochloride (0.73 g, 7.5 mmol), HOBt (1.0 g, 7.5 mmol), triethylamine (2.0 mL, 14 mmol) and WSC (1.4 g, 7.5 mmol) in DMF (28 mL) was stirred at room temperature overnight. The mixture was diluted with AcOEt, washed with water and brine, dried over MgSO4 and concentrated under reduced pressure to give the title compound (1.6 g, 58% yield) as a brown solid: 1H NMR (300 MHz, DMSO-d6): δ ppm 3.01-3.19 (4H, m), 3.24 (3H, s), 3.56 (3H, s), 3.62-3.91 (7H, m), 7.17 (1H, dd, J=12.7, 7.7 Hz), 7.62-7.82 (1H, m), 8.48 (1H, s). LC-MS (ESI) m/z 411 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14](Br)[C:15]#[CH:16].C(=O)([O-])[O-].[K+].[K+].[Br-]>C(#N)C.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:16][C:15]#[CH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: C#CCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 36 h
Yield: 44.7 %

Procedure:
To a solution of 10.0 g (54.8 mmol) of tert-butyl-1-piperazine carboxylate in 60 mL acetonitile was added 5.20 mL (60.4 mmol) propargyl bromide and 37.9 g (274 mmol) anhydrous potassium carbonate. Additional propargy bromide, 1.5 mL, was added after stirring for 36 hours at room temperature. The residue was evaporated to dryness. Dichloromethane, 50 mL, and water, 50 mL, were added. The reaction mixture was extracted with CH2Cl2, 4×40 mL, dried over magnesium sulfate, and evaporate to provide a brown oil. The oil was dissolved in dichloromethane and purify with a RT Scientific system using hexane/ethyl acetate gradient to yield 5.5 g (46%) of yellow oil, which ultimately crystallized upon standing.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH3:7])[CH2:3][C:4]#[CH:5].[C:8]1([C:14](Cl)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>N1C=CC=CC=1>[C:8]1([C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:1][CH:2]([CH2:6][CH3:7])[CH2:3][C:4]#[CH:5])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C#CCC(O)CC
Solvent: O
Solvent: c1ccncc1
Product: C#CCC(CC)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A stirred solution of 9.81 g (0.10 moles) of 4-hydroxy-1-hexyne and 33.5 g (0.12 moles) of triphenylmethyl chloride in 100 ml of dry pyridine is heated at reflux for 2 hours. The cooled mixture is treated with water and extracted with a hexane-ether mixture. The extract is washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. Column chromatography of the residue on Florisil gives an oil, max. 3290 (acetylenic hydrogen), 1600, 1030 and 705 cm-1 (triphenylmethoxy group).
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16](I)[CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:24]#[CH:25]>C(#N)C.C(N(CC)CC)C>[C:1]12([CH2:11][NH:12][C:13]([C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([C:25]#[C:24][CH2:23][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH:15]=3)=[O:22])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(I)ncc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC#Cc1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Cl)cn1
Reaction time: 0.75 h
Yield: 74.4 %

Procedure:
A suspension of N-(1-adamantylmethyl)-5-chloro-2-iodoisonicotinamide (Example2(i)) (0.43 g) and tert-butyl prop-2-ynylcarbamate, (0.31 g) in anhydrous acetonitrile (5 ml) and triethylamine (5 ml) was purged with nitrogen for 5 minutes and the copper (I) iodide (0.004 g) and bis-triphenyphosphine palladium dichloride (0.014 g) were added. The mixture was stirred under nitrogen for 0.75 hours. The mixture was concentrated and the residue was purified by chromatography on silica gel eluting with acetone:dichloromethane (1:19) to afford the sub-titled compound (0.34 g) as a yellow foam.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][N:4]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.CCN(C(C)C)C(C)C.[CH3:25][CH:26]([CH3:41])[CH2:27][CH:28]([C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=1)[CH2:29][NH2:30].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[Cl:1][C:2]1[C:6]([C:7]([NH:30][CH2:29][CH:28]([C:31]2[CH:32]=[CH:33][C:34]([C:37]([F:38])([F:39])[F:40])=[CH:35][CH:36]=2)[CH2:27][CH:26]([CH3:41])[CH3:25])=[O:9])=[CH:5][N:4]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: CC(C)CC(CN)c1ccc(C(F)(F)F)cc1
Reactant: O=C(O)c1cn(-c2ncccn2)nc1Cl
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CC(CNC(=O)c1cn(-c2ncccn2)nc1Cl)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 3-chloro-1-pyrimidin-2-yl-1H-pyrazole-4-carboxylic acid (50 mg, 0.22 mmol) in 1.0 mL of DMF is added sequentially DIEA (0.08 mL, 0.44 mmol), 4-methyl-2-[4-(trifluoro-methyl)phenyl]pentan-1-amine (54 mg, 0.22 mmol), and BOP (115 mg, 0.26 mmol). The resulting mixture is stirred at RT for 20 h. Water (3 mL) is added, and the mixture is extracted with CH2Cl2 (5 mL). The CH2Cl2 layer is dried (Na2SO4), filtered, and evaporated in vacuo. The residue is purified by silica gel column chromatography (gradient from 20% EtOAc/Hex to 60% EtOAc/Hex) to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.14 (1H, s), 8.89 (2H, d, J 4.8), 8.33 (1H, bs), 7.64 (2H, d, J 8), 7.55 (1H, t, J 4.8), 7.46 (2H, d, J 7.6), 3.44 (1H, m), 3.33 (1H, m), 3.07 (1H, m), 1.57 (1H, m), 1.51 (1H, m), 1.26 (1H, m), 0.81 (6H, d, J 6.4). MS (M+1)=452.14; RT=1.36 min. *IC50.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:31])[C:19]([C:25]3[N:26]=[C:27]([NH2:30])[S:28][CH:29]=3)=[N:20][O:21][CH2:22][CH2:23][NH2:24])[C:15](=[O:32])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].C([O-])(=O)C.[Na+:37]>CO.C(O)C>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:31])[C:19]([C:25]3[N:26]=[C:27]([NH2:30])[S:28][CH:29]=3)=[N:20][O:21][CH2:22][CH2:23][NH2:24])[C:15](=[O:32])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=[O:3])[CH3:2].[Na+:37]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCN)c3csc(N)n3)[C@H]2SC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NOCCN)c3csc(N)n3)[C@H]2SC1

Procedure:
The product of Example 34 was dissolved in 0.2 ml of a molar solution of sodium acetate in methanol and 0.4 ml of ethanol was slowly added thereto. The mixture was vacuum filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was taken up in ethanol and after efflorescence, the mixture was vacuum filtered to obtain 0.047 g of the syn isomer of sodium 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-(2-aminoethoxyimino)-acetamido]-ceph-3-eme-4-carboxylate.
Reaction SMILES: C([O:3][C:4](=[O:48])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH:25]=[C:26]([S:28]([CH:31]([CH3:33])[CH3:32])(=[O:30])=[O:29])[CH:27]=2)[C:10]=1[CH2:41][CH2:42][C:43]([O:45]CC)=[O:44])C.[OH-].[Na+]>>[C:43]([CH2:42][CH2:41][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:34]3[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=3)[CH:25]=[C:26]([S:28]([CH:31]([CH3:33])[CH3:32])(=[O:29])=[O:30])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:48])=[O:3])([OH:45])=[O:44]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccc(F)cc3)cc(S(=O)(=O)C(C)C)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CC(C)S(=O)(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(F)cc2)c1
Yield: 48.3 %

Procedure:
A similar procedure as described in Example 40, step 8 was used, starting from 4-[2-(2-ethoxycarbonyl-ethyl)-3-[6-(5-(propane-2-sulfonyl)-4′-fluoro-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid ethyl ester (180 mg, 0.26 mmol) and 1.0 N aqueous sodium hydroxide (2.6 mL) to afford 4-[2-(2-carboxy-ethyl)-3-[6-(5-(propane-2-sulfonyl)-4′-fluoro-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid (79 mg, 48%) as an amorphous white solid: ES(+)-HRMS m/e calcd for C34H41FO8S (M+Na)+ 651.2398, found 651.2395.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:26][C:8]2[C:9]3[CH:10]=[CH:11][C:12]([C:16](=[O:25])[NH:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:13][C:14]=3[S:15][C:7]=2[C:6]=1[O:27][CH2:28][C:29]([O:31]CC)=[O:30])=[O:4].O>C1COCC1>[CH2:18]([NH:17][C:16]([C:12]1[CH:11]=[CH:10][C:9]2[C:8]3[S:26][C:5]([C:3]([OH:4])=[O:2])=[C:6]([O:27][CH2:28][C:29]([OH:31])=[O:30])[C:7]=3[S:15][C:14]=2[CH:13]=1)=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)COc1c(C(=O)OC)sc2c1sc1cc(C(=O)NCc3ccccc3)ccc12
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COc1c(C(=O)O)sc2c1sc1cc(C(=O)NCc3ccccc3)ccc12
Yield: 56.6 %

Procedure:
Following General Procedure A, 6-benzylcarbamoyl-1-ethoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester (9 mg, 0.02 mmol) was stirred in THF (1 ml) and water (1 ml) for 17 hr. Work-up yielded 5 mg (63%) of title compounds as a light yellow solid.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11](=[O:25])[CH2:12][N:13]3[CH2:19][CH2:18][C:17]4[C:20](Cl)=[N:21][CH:22]=[N:23][C:16]=4[CH2:15][CH2:14]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C(OB([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)O)(=O)C.C([O-])([O-])=O.[Na+].[Na+].C[O:45][CH2:46][CH2:47]OC>O>[CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11](=[O:25])[CH2:12][N:13]3[CH2:19][CH2:18][C:17]4[C:20]([C:35]5[CH:34]=[CH:33][C:32]([C:46](=[O:45])[CH3:47])=[CH:37][CH:36]=5)=[N:21][CH:22]=[N:23][C:16]=4[CH2:15][CH2:14]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)OB(O)c1ccccc1
Reactant: COCCOC
Reactant: O=C(CN1CCc2ncnc(Cl)c2CC1)N1CCN(C2CCC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)c1ccc(-c2ncnc3c2CCN(CC(=O)N2CCN(C4CCC4)CC2)CC3)cc1
Temperature: 80 °C

Procedure:
A mixture of 7-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]-4-chloro-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine (55 mg, 0.15 mmol), acetylphenylboronic acid (37 mg, 0.22 mmol), Pd(PPh)4 (5.5 mg) and Na2CO3 (72 mg) in DME (3 mL) and water (1 mL) is heated overnight at 80° C. Water is added and the mixture is extracted with DCM. The combined organic layers are dried (MgSO4) and solvent removed in vacuo to give the crude product, which is purified by PTLC (5% MeOH in DCM) to give the title compound. 1H NMR (CDCl3) δ 8.99 (s, 1H), 8.04 (d, 2H), 7.55 (s, 2H), 3.54 (m, 4H), 3.33 (s, 2H), 3.20 (m, 2H), 2.97 (m, 2H), 2.94-2.66 (m, 5H), 2.64 (s, 3H), 2.26 (m, 4H), 2.04 (m, 2H), 1.88 (m, 2H), 1.68 (m, 2H).
Reaction SMILES: C1COCC1.[CH3:6][C:7]1([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH2:9][CH:8]1[C:10]([O:12]CC)=[O:11].[OH-].[Na+]>CO>[CH3:6][C:7]1([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=2)[CH2:9][CH:8]1[C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)C1CC1(C)c1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(c2ccc(C(F)(F)F)cc2)CC1C(=O)O
Yield: 94.4 %

Procedure:
The procedure described in Example 2I was followed using a THF (30 ml) solution of 14A (5.92 g, 21.7 mmol), 2M sodium hydroxide aqueous solution (22 ml) and MeOH (30 ml) to give 5.0 g (94% yield) of the title compound as white solids.
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]2)[O:3][CH2:2]1.[NH3:12].[H][H]>CO.[Pd]>[O:3]1[C:4]2([CH2:9][CH2:8][CH:7]([NH2:12])[CH2:6][CH2:5]2)[O:11][CH2:1][CH2:2]1
Reactant: N
Reactant: [H][H]
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Pd]
Solvent: CO
Product: NC1CCC2(CC1)OCCO2

Procedure:
To a solution of 9.36 g (60 mmol) 1,4-cyclohexanedione monoethylene acetal in 60 mL of methanol which has been saturated with ammonia, 0.6 g of palladium on carbon (10%) is added. The mixture is stirred overnight under 4 bar hydrogen pressure. Filtration over Celite and concentration in vacuum provides the crude product in almost quantitative yield.
Reaction SMILES: [Br-].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.O=[C:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38])[CH2:33][CH2:32]1.O>C1COCC1>[CH2:40]([O:39][C:37]([N:34]1[CH2:35][CH2:36][C:31](=[CH:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=2)[CH2:32][CH2:33]1)=[O:38])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Fc1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(=CCc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.2 %

Procedure:
To a suspension of phosphonium bromide 78NLS66 (4.69 g, 10.1 mmol) in THF (100 mL) n-butyllithium (1.6 M in hexane, 6.3 mL, 10.1 mmol) was added at 0° C., giving a deep red solution. After stirring for 1 h at rt, a solution of benzyl 4-oxo-1-piperidinecarboxylate (2.24 g, 9.6 mmol) in THF (10 mL) was added dropwise over 30 min. The mixture was stirred at rt for 20 h, then water was added and the mixture extracted three times with diethylether. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification of the residue by silica gel column chromatography, eluting with a stepwise gradient of 0-10% ethyl acetate in n-heptane, afforded the title compound (0.56 g, 17%) as a colourless oil.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=2[CH3:25])=[C:4]([CH:12]=[C:13]([F:16])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34]>C1COCC1>[F:1][C:2]1[C:3]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=2[CH3:25])=[C:4]([C:5]([NH:7][O:8][CH2:9][CH2:10][O:11][C:33](=[O:35])[CH3:34])=[O:6])[CH:12]=[C:13]([F:16])[C:14]=1[F:15]
Reactant: CC(=O)Cl
Reactant: Cc1cc(I)ccc1Nc1c(C(=O)NOCCO)cc(F)c(F)c1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCCONC(=O)c1cc(F)c(F)c(F)c1Nc1ccc(I)cc1C
Temperature: 2.5 °C
Reaction time: 0.08 h
Yield: 64.4 %

Procedure:
To a 0° C. solution of 3,4,5-trifluoro-N-(2-hydroxy-ethoxy)-2-(4-iodo-2-methyl-phenylamino)-benzamide (0.25 g, 0.536 mmol) in THF (10.72 mL) was added triethylamine (0.113 mL, 0.804 mmol). After 5 min, acetyl chloride (0.039 mL, 0.536 mmol) was added to the cold solution, which immediately produced a precipate. After stirring for 50 min between 0-5° C., the reaction mixture was partitioned between water (20 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL). The organic layers were combined and dried over anhydrous magnesium sulfate. The resultant mixture was filtered and the filter cake was thoroughly rinsed with ethyl acetate. The filtrate was concentrated in vacuo to obtain a yellow oil (0.1755 g). Chromatographed crude oil using a gradient of hexanes and ethyl acetate. Combined fractions and removed the solvent in vacuo to obtain a solid. The solid was recrystalized in a mixture of hexanes/acetone to afford 0.0221 g (8%) of a solid; 1H NMR (400 MHz, Acetone-d6): δ 10.15 (br s, 1H), 8.49 (br s, 1H), 7.88 (t, J=0.9 Hz, 1H), 7.56 (s, 1H), 7.43 (d, J=8.3 Hz, 1H), 6.69 (dd, J=8.55, 5.86 Hz, 1H), 4.53 (br s, 2H), 4.19 (br s, 2H), 2.33 (s, 3H), 1.81 (br s, 3H). 19F NMR (375 MHz, Acetone-d6): δ −139.52 (br t, 1F), −146.62 (br q, 1F), −153.43 (br s, 1F). Anal. Calcd/Found for C18H16F3IN2O4: C, 42.54/40.87; H, 3.17/2.98; N, 5.51/5.17.