Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][C@H:13]([CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)[CH:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:23].[C:24]1([C:34](O)=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:18]1([CH2:17][C@@H:13]([O:12][C:11]2[CH:10]=[CH:9][C:8]3[C:7](=[O:23])[CH2:6][CH2:5][CH2:4][C:3]=3[C:2]=2[NH:1][C:34]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][N:25]=2)=[O:35])[CH:14]([CH3:16])[CH3:15])[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: O=C(O)c1nccc2ccccc12
Reactant: CC(C)[C@@H](Cn1ccnc1)Oc1ccc2c(c1N)CCCC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)[C@@H](Cn1ccnc1)Oc1ccc2c(c1NC(=O)c1nccc3ccccc13)CCCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
To a solution of 5-amino-6-((S)-1-imidazol-1-ylmethyl-2-methyl-propoxy)-3,4-dihydro-2H-naphthalen-1-one (105 mg, 0.335 mmol) and 1-isoquinoline carboxylic acid (70 mg, 0.402 mmol) in DMF (3 mL) was added Et3N (56 μL, 0.402 mmol) followed by HATU (153 mg, 0.402 mmol). The reaction was stirred at RT overnight. The DMF was removed under reduced pressure. The residue was diluted with EtOAc and washed with H2O, saturated aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated. Purification by chromatography (5% MeOH/EtOAc with 1% NH4OH) afforded the title compound as a foam (66 mg, 0.141 mmol, 42%). The structure was confirmed by NMR and mass spectrometry. MS m/z 469 (M++H).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[CH:20]1[C:33]2[C:32](=[C:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[S:25][C:24]=2[CH:23]=[CH:22][CH:21]=1.[C:40]([O:44][C:45]([NH:47][C@H:48]([C:53]([O:55][CH3:56])=[O:54])[CH2:49][C:50](O)=[O:51])=[O:46])([CH3:43])([CH3:42])[CH3:41].[Cl-].[NH4+]>ClCCl>[C:40]([O:44][C:45]([NH:47][C@H:48]([CH2:49][C:50](=[O:51])[N:37]1[CH2:38][CH2:39][C:34](=[C:32]2[C:33]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[S:25][C:26]3[C:31]2=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:35][CH2:36]1)[C:53]([O:55][CH3:56])=[O:54])=[O:46])([CH3:43])([CH3:42])[CH3:41]
Reactant: c1ccc2c(c1)Sc1ccccc1C2=C1CCNCC1
Reactant: COC(=O)[C@H](CC(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](CC(=O)N1CCC(=C2c3ccccc3Sc3ccccc32)CC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.00 g (5.22 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride, 0.73 ml (5.24 mmol) of triethylamine and 1.351 g (4.84 mmol) of 4-(9H-thioxanthen-9-ylidene)piperidine were added to 1.290 g (5.22 mmol) of (S)-3-[(t-butoxycarbonyl)amino]-4-methoxy-4-oxobutanoic acid in 20 ml of dichloromethane in an ice bath, and they were stirred at room temperature overnight. Saturated aqueous ammonium chloride solution was added to the reaction mixture. After extracting with dichloromethane, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by the silica gel chromatography (hexane:ethyl acetate=7:3 to 1:1) to obtain the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([OH:19])=[O:18])=[CH:3][CH:2]=1.[CH2:20]([N:22]([CH2:28][CH3:29])[C:23](=[O:27])[O:24][CH2:25]Cl)[CH3:21].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:20]([N:22]([CH2:28][CH3:29])[C:23]([O:24][CH2:25][O:18][C:17]([C:9]1[NH:10][C:11]2[C:16]([C:8]=1[NH:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:19])=[O:27])[CH3:21]
Reactant: O=C(O)c1[nH]c2ccccc2c1Nc1ccncc1
Reactant: CCN(CC)C(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)OCOC(=O)c1[nH]c2ccccc2c1Nc1ccncc1
Yield: 36 %

Procedure:
Stir a mixture of 3-(4-pyridinylamino)-1H-indole-2-carboxylic acid (2.0 g, 8.0 mmol), chloromethyl diethylcarbamate (1.7 g, 10.4 mmol) and K2CO3 in DMF (50 mL) at ambient temperature overnight. Add EtOAc (400 mL), to the reaction mixture, wash the organic layer with brine solution (400 mL) and concentrate to an oil. Purify by flash chromatography over silica gel (40 g) eluting with EtOAc and then 10% MeOH/EtOAc. Collect like fractions and concentrate under vacuum to yield an oil. Crystallize from heptane-ether to obtain 1.1 g (36%) of the title compound as a white powder: MS 383(M+H).
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7]O)=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:4][N:3]=1.CS([Cl:21])(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:6]([CH2:7][Cl:21])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:4][N:3]=1
Reactant: COc1ccc(-c2snc(Cl)c2CO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COc1ccc(-c2snc(Cl)c2CCl)cc1
Temperature: 0 °C

Procedure:
Into a 100-mL round-bottom flask, was placed [3-chloro-5-(4-methoxyphenyl)-1,2-thiazol-4-yl]methanol (223 mg, 0.87 mmol, 1.00 equiv), dichloromethane (20 mL), TEA (261 mg, 2.58 mmol, 2.96 equiv). This was followed by the addition of MsCl (200 mg) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at room temperature. The resulting solution was diluted with 40 mL of DCM. The resulting mixture was washed with 3×10 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 430 mg (crude) of 3-chloro-4-(chloromethyl)-5-(4-methoxyphenyl)-1,2-thiazole as yellow oil.
Reaction SMILES: Cl[C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14]([N+:16]([O-:18])=[O:17])=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.Br.[NH:20]([C:22]1[S:23][CH2:24][CH2:25][N:26]=1)[NH2:21].C([O-])(=O)C.[Na+]>CO>[S:23]1[CH2:24][CH2:25][NH:26][C:22]1=[N:20][N:21]=[C:2]1[C:15]2[C:14]([N+:16]([O-:18])=[O:17])=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: NNC1=NCCS1
Reactant: O=[N+]([O-])c1cccc2nc3ccccc3c(Cl)c12
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1cccc2[nH]c3ccccc3c(=NN=C3NCCS3)c12
Reaction time: 8 h

Procedure:
5.0 g of 9-chloro-1-nitroacridine, 3.8 g of 2-hydrazino-2-thiazoline hydrobromide and 3.17 g of anhydrous sodium acetate are dissolved in 250 ml of dry methanol, heated on a steam-bath for 1 hour and then left to stand overnight. The precipitated material is filtered and recrystallized from methanol. There is obtained 1-nitro-9-acridanone (2-thiazolidinylidene)hydrazone which beings to decompose from 152°.
Reaction SMILES: C[N:2]1CCOCC1.[CH3:8][S:9][C:10]1[N:15]=[C:14]([C:16](O)=[O:17])[CH:13]=[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:11]=1.[Cl-].[NH4+].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH3:8][S:9][C:10]1[N:15]=[C:14]([C:16]([NH2:2])=[O:17])[CH:13]=[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:11]=1
Reactant: CSc1nc(C(=O)O)cc(-c2ccccc2)n1
Reactant: CN1CCOCC1
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CSc1nc(C(N)=O)cc(-c2ccccc2)n1
Yield: 94.1 %

Procedure:
N-Methylmorpholine (2.31 mL, 21 mmol) was added dropwise by syringe to a mixture of 2-methylsulfanyl-6-phenylpyrimidine-4-carboxylic acid (3.45 g, 14 mmol), ammonium chloride (4.27 g, 80 mmol), HOBt (2.84 g, 21 mmol), and EDC (4.0 g, 21 mmol) in DMF (40 mL) at room temperature. The reaction solution was stirred at room temperature for 3 h before the DMF was removed by rotary evaporation. Column chromatography (SiO2, DCM/EtOAc 5:1) afforded 3.23 g of 2-(methylthio)-6-phenylpyrimidine-4-carboxamide as a white solid. 1H NMR (DMSO-d6, 300 MHz) δ 8.25 (m, 2H), 8.13 (s, 1H), 7.59 (m, 3H), 2.62 (s, 3H). HPLC ret. time 2.71 min, 10-100% CH3CN, 5 min gradient. ESI-MS m/z 246.1 (M+H)+.
Reaction SMILES: Br[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH2:13][CH3:14])[CH:5]=1)=[CH2:3].[Li]C(C)(C)C.[CH:20]([CH:22]=[CH2:23])=[O:21]>>[CH2:13]([O:12][C:6]1[CH:5]=[C:4]([C:2]([CH:20]([OH:21])[CH:22]=[CH2:23])=[CH2:3])[CH:9]=[CH:8][C:7]=1[O:10][CH3:11])[CH3:14]
Reactant: C=CC=O
Reactant: C=C(Br)c1ccc(OC)c(OCC)c1
Agent: [Li]C(C)(C)C
Product: C=CC(O)C(=C)c1ccc(OC)c(OCC)c1
Yield: 86.2 %

Procedure:
According to the General Procedure C, 1-bromo-1-(3-ethoxy-4-methoxyphenyl)ethene (1.40 g, 5.44 mmol), t-BuLi (8.00 ml, 13.60 mmol) and acrolein (914 mg, 16.32 mmol) are converted to give after workup and chromatography [SiO2, PE/EE gradient from 5:1 to 2:1, Rf (PE/EE=2:1)=0.31] the title compound (1.10 g, 4.69 mmol) as a colorless oil;
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([N:9](C=O)[CH2:10][C@@H:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][C:24]4=[O:29])=[CH:19][CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1.ClCCl.Cl>CO>[CH:19]1[C:20]([N:23]2[C:24](=[O:29])[CH2:25][O:26][CH2:27][CH2:28]2)=[CH:21][CH:22]=[C:17]([N:13]2[C:14](=[O:16])[O:15][C@@H:11]([CH2:10][NH:9][C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:8])[CH2:12]2)[CH:18]=1
Reactant: O=CN(C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)C(=O)c1ccc(Cl)s1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: O=C(NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1

Procedure:
In four neck round bottom flask charge 5-chloro-N-formyl-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide (120 g), dichloromethane (2400 ml) and hydrochloric acid OR sulphuric acid (120 ml) at 25-30° C. Obtained reaction mixture is heated to reflux for 4 to 5 h. After completion of reaction, concentrate reaction mass under reduced pressure to obtain residue. Added Dichloromethane (120 ml) and slowly added Methanol (600 ml) to the residue. The precipitated solid is filtered off and washed by methanol (240 ml)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[C:19](I)=[CH:18][CH:17]=[C:16]3[O:21][CH2:22][O:23][C:15]=13)=[CH:10][C:9]([O:24][CH3:25])=[C:8]([O:26][CH3:27])[CH:7]=2)#[N:2].[C:28](C1C=NC2C(C=1NC1C(I)=CC(I)=C3OCOC=13)=CC(OC)=C(OC)C=2)#[N:29]>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].[C-]#N.[Zn+2].[C-]#N.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2].[Zn].CC(N(C)C)=O>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[C:19]([C:28]#[N:29])=[CH:18][CH:17]=[C:16]3[O:21][CH2:22][O:23][C:15]=13)=[CH:10][C:9]([O:24][CH3:25])=[C:8]([O:26][CH3:27])[CH:7]=2)#[N:2]
Reactant: COc1cc2ncc(C#N)c(Nc3c(I)cc(I)c4c3OCO4)c2cc1OC
Reactant: COc1cc2ncc(C#N)c(Nc3c(I)ccc4c3OCO4)c2cc1OC
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Product: COc1cc2ncc(C#N)c(Nc3c(C#N)ccc4c3OCO4)c2cc1OC
Temperature: 110 °C

Procedure:
Tris(dibenzylideneacetone)dipalladium (0.039 g) was added to a mixture of a 4:1 mixture (0.25 g) of 3-cyano-4-(6-iodo-2,3-methylenedioxyanilino)-6,7-dimethoxyquinoline and 3-cyano-4-(4,6-diiodo-2,3-methylenedioxyanilino)-6,7-dimethoxyquinoline (Example 10, Note [11]), zinc cyanide (0.092 g), diphenylphosphinoferrocene (0.046 g), zinc powder (0.017 g) and DMA (15 ml) and the resultant mixture was stirred and heated to 110° C. for 1 hour. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulphate and evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of hexane and ethyl acetate as eluent. There were thus obtained in turn:—
Reaction SMILES: [CH3:1][C:2]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[NH:21][C:20](=[O:28])[C:4]2([CH2:9][CH2:8][N:7](C(OCC3C=CC=CC=3)=O)[CH2:6][CH2:5]2)[N:3]=1>C(O)C.[Pd]>[CH3:1][C:2]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[NH:21][C:20](=[O:28])[C:4]2([CH2:5][CH2:6][NH:7][CH2:8][CH2:9]2)[N:3]=1
Reactant: CC1=NC2(CCN(C(=O)OCc3ccccc3)CC2)C(=O)Nc2ccccc21
Agent: [Pd]
Solvent: CCO
Product: CC1=NC2(CCNCC2)C(=O)Nc2ccccc21

Procedure:
6.0 g (0.016 mole) of 5-methyl-1'-benzyloxycarbonyl-spiro-[1H-1,4-benzodiazepine-3,4'-piperidin]-2(3H)-one are hydrogenated in 250 ml of ethanol in the presence of 0.5 g of palladium-on-charcoal at 20° C. After the catalyst has been removed by filtration, the filtrate is concentrated and, after addition of diethyl ether, the residue crystallizes.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:42][C:43]([N:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1)=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:42][CH2:43][N:45]2[CH2:49][CH2:48][CH2:47][CH2:46]2)=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: O=C(CCl)N1CCCC1
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN2CCCC2)c(F)c1)c1cc(OC)c(OC)cc1C1CCc2cc(O)ccc2C1
Yield: 8.4 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 2-chloro-1-pyrrolidin-1-ylethanone (10 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (1.6 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:16]3[CH2:20][CH2:19][N:18]([C:21]4[CH:22]=[N:23][N:24]([C:29]5[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=5)[C:25]=4[CH:26]([CH3:28])[CH3:27])[C:17]3=[O:36])[N:9]=[C:10]([C:11]3[NH:12][CH2:13][CH2:14][N:15]=3)[C:3]=12.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>CS(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:16]3[CH2:20][CH2:19][N:18]([C:21]4[CH:22]=[N:23][N:24]([C:29]5[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=5)[C:25]=4[CH:26]([CH3:27])[CH3:28])[C:17]3=[O:36])[N:9]=[C:10]([C:11]3[NH:12][CH:13]=[CH:14][N:15]=3)[C:3]=12
Reactant: CC(C)c1c(N2CCC(n3nc(C4=NCCN4)c4c(N)ncnc43)C2=O)cnn1-c1ccc(F)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CS(C)=O
Product: CC(C)c1c(N2CCC(n3nc(-c4ncc[nH]4)c4c(N)ncnc43)C2=O)cnn1-c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 60 %

Procedure:
A mixture of 3-[4-amino-3-(4,5-dihydro-1H-imidazol-2-yl)pyrazolo[3,4-d]pyrimidin-1-yl]-1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-yl]pyrrolidin-2-one (0.057 g, 0.12 mmol) and Dess-Martin periodinane (0.100 g, 0.23 mmol) in DMSO (3 mL) was stirred at 80° C. for 45 min. The mixture was then cooled to room temperature, quenched with sat. aq. NaHCO3 (50 mL), and extracted with EtOAc (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to yield the title compound (0.035 g, TFA salt, 48%). 1H NMR (TFA salt) (400 MHz, CDCl3) δ 11.96 (s, 1H), 11.12 (s, 1H), 8.17 (s, 1H), 7.65 (s, 1H), 7.40 (dd, J=8.8, 4.4 Hz, 2H), 7.20 (dd, J=8.6, 8.6 Hz, 1H), 7.05 (s, 2H, br), 5.74 (dd, J=9.2, 9.2 Hz, 1H) 3.94 (dd, J=8.4, 4.4 Hz, 2H), 3.05 (m, 1H), 3.07 (septet, J=7.0 Hz, 1H), 2.87 (m, 2H), 1.31 (d, J=6.8 Hz, 3H), 1.27 (d, J=6.8 Hz, 3H); MS: (ES) m/z calculated for C24H23FN10O (free form) [M+H]+ 487.2. found 487.2.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:36]([CH3:37])=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][C:5]=1[CH3:38].[N+:39]([C:42]1[CH:47]=[CH:46][C:45]([N:48]=[C:49]=[O:50])=[CH:44][CH:43]=1)([O-:41])=[O:40].C(N(CC)CC)C.O1CCCC1>CN(C)C=O>[O:29]=[C:27]1[NH:26][C:25](=[O:30])[CH:24]([CH2:23][C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:15]3[N:14]([CH3:33])[C:13]4[CH:34]=[C:9]([O:8][C:7]5[CH:6]=[C:5]([CH3:38])[C:4]([NH:3][C:49]([NH:48][C:45]6[CH:44]=[CH:43][C:42]([N+:39]([O-:41])=[O:40])=[CH:47][CH:46]=6)=[O:50])=[C:36]([CH3:37])[CH:35]=5)[CH:10]=[CH:11][C:12]=4[N:16]=3)=[CH:32][CH:31]=2)[S:28]1
Reactant: Cc1cc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc(C)c1N
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc(C)c1NC(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 54.6 %

Procedure:
A mixture of 5-[4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (288 mg), 4-nitrophenyl isocyanate (98 mg), triethylamine (121 mg), anhydrous tetrahydrofuran (10 ml) and anhydrous N,N-dimethylformamide (10 ml) was stirred at room temperature for 23 hours. The reaction mixture was concentrated and diluted with water. The precipitate was isolated by filtration and then chromatographed on a silica gel column using ethyl acetate as the eluant to afford the title compound (182 mg, mp 178-180° C.).
Reaction SMILES: C([O:3][C:4](=[O:38])[C@@H:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C@H:19]([N:26]([C:34](=[O:36])[CH3:35])[C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[CH2:18][CH:17]2[CH3:37])=[O:15])=[CH:10][CH:9]=1)[F:6])C.[OH-].[K+]>CO.C1COCC1>[C:34]([N:26]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C@H:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:16]([C:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][C@@H:5]([F:6])[C:4]([OH:38])=[O:3])=[CH:9][CH:10]=2)=[O:15])[CH:17]([CH3:37])[CH2:18]1)(=[O:36])[CH3:35]
Reactant: CCOC(=O)[C@H](F)Oc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)CC2C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1CC(C)N(C(=O)c2ccc(O[C@@H](F)C(=O)O)cc2)c2ccccc21
Reaction time: 1 h

Procedure:
(2S,4R)-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-fluoro-acetic acid ethyl ester (100 mg) was dissolved in methanol/THF (1:1, 5 mL), and potassium hydroxide (1.0N, 1 mL) was added. After 1 hour, the reaction was acidified and extracted with methylene chloride. The organic layer was dried, filtered, and concentrated. The crude residue was purified by silica gel chromatography 100% ethyl acetate to 5% methanol/ethyl acetate gradient to afford the product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:14][CH2:13][CH2:12][O:11]2)[CH:5]=[C:4]([CH3:15])[C:3]=1[C:16]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]2[C:17]=1[CH2:18][CH2:19][C@H:20]2[O:26][C:27]1[CH:40]=[CH:39][C:30]2[C@H:31]([CH2:34][C:35]([O:37]C)=[O:36])[CH2:32][O:33][C:29]=2[CH:28]=1>C(O)(C)C>[CH3:15][C:4]1[CH:5]=[C:6]([O:8][CH2:9][CH:10]2[CH2:14][CH2:13][CH2:12][O:11]2)[CH:7]=[C:2]([CH3:1])[C:3]=1[C:16]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]2[C:17]=1[CH2:18][CH2:19][C@H:20]2[O:26][C:27]1[CH:40]=[CH:39][C:30]2[C@H:31]([CH2:34][C:35]([OH:37])=[O:36])[CH2:32][O:33][C:29]=2[CH:28]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCC6CCCO6)cc5C)ccc(F)c43)ccc21
Solvent: CC(C)O
Product: Cc1cc(OCC2CCCO2)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O

Procedure:
The title compound is prepared from methyl 2-((3S)-6-((1R)-4-(2,6-dimethyl-4-((tetrahydrofuran-2-yl)methoxy)phenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate following a procedure analogous to that described in example 1. Isopropanol is used instead of methanol. LC (method 1): tR=1.42 min; Mass spectrum (ESI+): m/z=533 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH2:19][OH:20])[C:8]2[CH:9]([OH:18])[C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:4].[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOC(C)=O.CCCCCC>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH2:19][O:20][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][O:21]2)[C:8]2[CH:9]([OH:18])[C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:4]
Reactant: COC(=O)c1cc(CO)c2c(c1)-c1ccccc1C2O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1cc(COC2CCCCO2)c2c(c1)-c1ccccc1C2O

Procedure:
3-Methoxycarbonyl-1-hydroxymethyl-9-fluorenol (0.96 g) was treated with dihydropyran (0.43 ml) and p-toluenesulfonic acid (20 mg) in CH2Cl2 (20 ml) for 0.5 hour. The reaction mixture was washed once with NaHCO3 (10% soln) then dried and evaporated to give a mixture of products. Chromatography on silica gel using EtOAc/hexane 1:1 as eluant gave the product (403 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[C:16]([CH:18]([CH2:22][CH3:23])[C:19](Cl)=[O:20])#[N:17].C(N(CC)CC)C>CC(C)=O>[C:16]([CH:18]([CH2:22][CH3:23])[C:19]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:20])#[N:17]
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: CCC(C#N)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCC(C#N)C(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1
Temperature: 0 °C
Yield: 49.9 %

Procedure:
20.3 g (0.1 mole) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone were stirred with 15.8 g (0.12 mole) of 2-cyanobutyryl chloride and 10.1 g (0.1 mole) of triethylamine in 200 ml of absolute acetone for 3 hours at room temperature. 100 g of ice were added, after which the crystals were filtered off under suction, and the product was recrystallized from dimethylformamide/water and dried at 50° C. under greatly reduced pressure. 14.9 g (50%) of 6-[p-(2-cyanobutyrylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone were obtained. Mp.: 225°-227° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C@H:8]1[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:17][CH2:18]Br)[C@@H:12]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:11]([CH3:27])[O:10][C:9]1=[O:28])([CH3:4])([CH3:3])[CH3:2].CC(N=NC(C#N)(C)C)(C#N)C.CCCC[SnH](CCCC)CCCC.[F-].[K+]>C1(C)C=CC=CC=1.CC(C)=O>[C:1]([O:5][C:6](=[O:29])[NH:7][C@H:8]1[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:17][CH3:18])[C@@H:12]([O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@H:11]([CH3:27])[O:10][C:9]1=[O:28])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H]1OC(=O)[C@@H](NC(=O)OC(C)(C)C)CCC[C@H](CCBr)[C@H]1Oc1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: CC[C@H]1CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@@H](C)[C@@H]1Oc1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a solution of tert-butyl((3S,7R,8R,9S)-7-(2-bromoethyl)-9-methyl-2-oxo-8-phenoxyoxonan-3-yl)carbamate (408 mg, 0.867 mmol) and AIBN (14.24 mg, 0.087 mmol) in anhydrous toluene (8.7 mL) was added Bu3SnH (257 μl, 0.954 mmol), and the reaction was heated to 80° C. After 1 h, TLC (4:1 hexanes: acetone) still showed starting material. An additional 0.5 equivalents of Bu3SnH and 0.05 equiv AIBN were added and the reaction was stirred for an additional 1 h at 80° C. The reaction was cooled to room temperature, stirred with 10% aqueous potassium fluoride (KF) solution (7 mL) for 20 h, and partitioned between Et2O (20 mL) and sat. NaCl solution (20 mL). The phases were separated and the aqueous phase was extracted with Et2O (2×20 mL). The organic extracts were combined, dried over MgSO4, filtered and concentrated to provide a white solid, which was purified by column chromatography on SiO2 (5→20% acetone/hexanes) to provide the title compound as a white solid (295 mg, 87%): 1H NMR (400 MHz, CDCl3) δ 7.38-7.16 (m, 2H), 7.00-6.87 (m, 3H), 5.19-4.97 (m, 2H), 4.18 (t, J=8.8 Hz, 2H), 2.27 (dt, J=13.1, 6.7 Hz, 1H), 1.91-1.77 (m, 1H), 1.70-1.58 (m, 3H), 1.58-1.48 (m, 1H), 1.44 (s, 9H), 1.28 (d, J=6.5 Hz, 3H), 1.25-1.14 (m, 2H), 1.12-1.01 (m, 1H), 0.86 (t, J=7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 173.34, 159.68, 154.91, 129.58, 120.95, 115.40, 81.44, 79.86, 74.74, 53.00, 44.96, 34.20, 28.34, 27.85, 27.03, 26.85, 23.50, 18.74, 18.40, 17.53, 13.61, 11.86; ESIMS m/z 392.3 ([M+H]+), 414.3 ([M+Na]+).