Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]1([O-])C2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH:4]=[CH:3]C=1.[NH3:13].[C:14]([O:17][C:18](=[O:20])[CH3:19])(=O)[CH3:15]>>[C:18]([O:17][C:14]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[NH:13][C:9](=[O:11])[CH:8]=[CH:7]2)(=[O:20])[CH3:19]
Reactant: N
Reactant: CC(=O)OC(C)=O
Reactant: [O-][n+]1cccc2cccc(O)c21
Product: CC(=O)Oc1cccc2ccc(=O)[nH]c12

Procedure:
Quinolin-8-ol 1-oxide (20 g, 124 mmol) in acetic anhydride (200 ml) was stirred at 90° C. for 5 hours. Then the reaction mixture was poured into water/ice mixture (1.5 L), and made neutral by addition of conc. aq. NH3. The precipitate formed was collected by filtration and washed with water. The crude product was purified by suspending in propan-2-ol and addition of petroleum ether to give 2-oxo-1,2-dihydroquinolin-8-yl acetate. 2-Oxo-1,2-dihydroquinolin-8-yl acetate was heated in conc. aq. HCl (200 ml) at 90° C. for 4 hours. The reaction mixture was poured into ice-cold water (400 ml), and the precipitate formed was collected by filtration and washed with water. Recrystallization from propan-2-ol/petroleum ether afforded the subtitle compound (14.1 g, 70%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:15]1[C:23]2[C:18](=[N:19][CH:20]=[N:21][C:22]=2[NH2:24])[N:17]([C@@H:25]2[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]2)[N:16]=1.[C:31]([CH2:33][C:34](O)=[O:35])#[N:32].N1(C(N2C=CN=C2)=O)C=CN=C1>ClCCl>[NH2:24][C:22]1[N:21]=[CH:20][N:19]=[C:18]2[N:17]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:34](=[O:35])[CH2:33][C:31]#[N:32])[CH2:26]3)[N:16]=[C:15]([C:3]3[CH:4]=[CH:5][C:6]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:7][C:2]=3[F:1])[C:23]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1F)nn2[C@@H]1CCCNC1
Reactant: N#CCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.1 %

Procedure:
Into a 100 mL round-bottom flask, was placed a solution of 3-(2-fluoro-4-phenoxyphenyl)-1-[(3R)-piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (190 mg, 0.47 mmol, 1.00 equiv) in dichloromethane (50 mL), 2-cyanoacetic acid (60 mg, 0.71 mmol, 1.50 equiv), and 1-[(1H-imidazol-1-yl)carbonyl]-1H-imidazole (114 mg, 0.70 mmol, 1.50 equiv). The resulting solution was stirred for 24 h at room temperature and then diluted with dichloromethane. The resulting mixture was washed with NH4Cl and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100:1) to give 100 mg (45%) of 3-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.Br[CH2:12][C:13](=[O:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:15]=[C:13]([CH3:14])[CH2:12][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1
Reactant: CC(=O)CBr
Reactant: OCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)COc1ccc(CCO)cc1

Procedure:
Following a procedure similar to that described in Preparation 3, but using 10 g of 2-(4-hydroxyphenyl)-ethanol, 21.6 g of bromoacetone, 30 g of potassium carbonate and 100 ml of dimethylformamide, the title compound was obtained having an Rf=0.31 (thin layer chromatography over silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C([N:12]1[CH2:16][CH2:15][NH:14][C:13]1=O)(=O)C>O=P(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:13]1[NH:14][CH2:15][CH2:16][N:12]=1
Reactant: CC(=O)N1CCNC1=O
Reactant: Nc1ccccc1Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ccccc1NC1=NCCN1

Procedure:
12.75 g of o-chloroaniline and 14.09 g of 1-acetylimidazolidin-2-one in 144 ml of POCl3 are stirred for 71 hours at 60°C. The mixture is worked up as described in Example 19 and 15.45 g, that is to say 65.3%, of the acetyl derivative of 2-(2'-chlorophenylamino)-2-imidazoline are obtained as a crystalline product, which, for analysis, is recrystallised from i-propanol and toluene. Melting point: 142°-143°C
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:29][CH2:28][C:11]3([CH2:15][N:14](C(OC(C)(C)C)=O)[C@H:13]([C:23]([O:25]CC)=[O:24])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:30][C@H:31]([C:36]2[CH:41]=[C:40]([CH2:42][CH2:43][CH3:44])[CH:39]=[CH:38][C:37]=2[C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([S:51]([CH3:54])(=[O:53])=[O:52])[CH:46]=2)[C:32]([F:35])([F:34])[F:33])[N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][NH:14][C@H:13]([C:23]([OH:25])=[O:24])[CH2:12]3)[CH2:28][CH2:29]2)[CH:5]=[C:4]([O:30][C@H:31]([C:36]2[CH:41]=[C:40]([CH2:42][CH2:43][CH3:44])[CH:39]=[CH:38][C:37]=2[C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([S:51]([CH3:54])(=[O:53])=[O:52])[CH:46]=2)[C:32]([F:35])([F:33])[F:34])[N:3]=1
Reactant: CCCc1ccc(-c2cccc(S(C)(=O)=O)c2)c([C@@H](Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)OCC)N(C(=O)OC(C)(C)C)C4)nc(N)n2)C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1ccc(-c2cccc(S(C)(=O)=O)c2)c([C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(methylsulfonyl)-4-propyl-[1,1′-biphenyl]-2-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate in CH2Cl2 (4 mL) was added TFA (2.0 mL) dropwise at 0° C. The reaction mixture was stirred at RT for 2 h, then concentrated in vacuo. The pH was adjusted to 7-8 with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (CH2Cl2/MeOH) provided the title compound as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:20])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:7][CH2:6]1.[O:21]=[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([S:32](Cl)(=[O:34])=[O:33])=[CH:24][NH:23]1.S(Cl)(Cl)(=O)=O>N1C=CC=CC=1>[C:12]([OH:21])(=[O:11])[CH3:17].[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[O:11][CH:8]1[CH2:9][CH2:10][N:5]([CH2:4][C@H:3]([OH:20])[CH2:2][NH:1][S:32]([C:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:22](=[O:21])[NH:23][CH:24]=2)(=[O:33])=[O:34])[CH2:6][CH2:7]1
Reactant: O=c1[nH]cc(S(=O)(=O)Cl)c2ccccc12
Reactant: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Solvent: c1ccncc1
Solvent: O=S(=O)(Cl)Cl
Product: CC(=O)O
Product: O=c1[nH]cc(S(=O)(=O)NC[C@@H](O)CN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.3 %

Procedure:
(2R)-1-Amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.1 g) in pyridine (2 ml) was treated with 1-oxo-1,2-dihydroisoquinoline-4-sulfonyl chloride (0.11 g) and the mixture was stirred at ambient temperature for 18 h. After further additions of the sulfonyl chloride (0.05 g) and stirring for 24 h the solvent was evaporated. Purification by column chromatography and reverse phase HPLC (symmetry C8 column and acetonitrile/0.1% aqueous ammonium acetate) yielded the title compound as a white solid (0.06 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)=[C:20]([CH:33]=2)[C:21]([NH:23][C@@H:24]([CH2:29][CH2:30][S:31][CH3:32])[C:25]([O:27]C)=[O:26])=[O:22])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:34][CH2:35][C:36]3[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=3)=[C:20]([CH:33]=2)[C:21]([NH:23][C@@H:24]([CH2:29][CH2:30][S:31][CH3:32])[C:25]([OH:27])=[O:26])=[O:22])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1cc(OC(Cn2ccnc2)c2ccc(F)cc2)ccc1CCc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CSCC[C@H](NC(=O)c1cc(OC(Cn2ccnc2)c2ccc(F)cc2)ccc1CCc1ccc(F)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 30.9 %

Procedure:
A solution of methyl (2S)-2-{5-[1-(4-fluorophenyl)-2-(imidazol-1-yl)ethoxy]-2-(4-fluorophenethyl)benzoylamino}-4-methylsulfanylbutyrate (140 mg, 0.24 mmol) in methanol (5 ml) was treated with sodium hydroxide (190 mg, 4.7 mmol) in water (1 ml) and the mixture stirred at ambient temperature for 6 hours. The mixture was acidified to PH1 with 1M HCl and evaporated to dryness. The residue was washed with water (3×2 mL) and the resulting gum was triturated with diethyl ether to give the title compound as a white solid (43 mg). 1H NMR (DMSO-d6, 300 MHz) δ: 1.85-2.05 (5H,m); 2.4-2.6 (signed partially obscured by solvent signals, m); 2.6-2.75 (2H,m); 2.75-2.86 (2H,m); 4.4-4.48 (1H, m); 4.64.7 (2H,m); 5.82 (1H,t); 6.76-6.86 (2H,m); 6.96-7.08 (3H,m); 7.12-7.28 (4H,m); 7.44-7.5 (2H,dd); 7.62 (1H,s); 7.69 (1H,s); 8.58 (1H,t); 9.12 (1H,s). MS (ES+) m/z 580.3 (MH+) Anal.calculated for C31H31F2N3O4S.HCl.0.9NaCl C, 55.7; H, 4.8; N, 6.3%; Found: C, 55.9; H, 4.8; N, 6.1%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH:22]=O.Cl.[NH2:25][OH:26].C(N(CC)CC)C>C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH:22]=[N:25][OH:26]
Reactant: CSc1ccc(/C=C2/C(C)=C(CC=O)c3cc(F)ccc32)cc1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CSc1ccc(/C=C2/C(C)=C(CC=NO)c3cc(F)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of the acetaldehyde derivative from Step 2 (3.3 g, 10.18 mmol), hydroxylamine hydrochloride (1.42 g, 20.4 mmol), ethanol (25 mL) and triethylamine (2.06 g, 20.4 mmol) was stirred at room temperature for 30 minutes. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The crude product from the organic phase was purified by column chromatography on silica gel using a 1:2 mixture of ethyl acetate:hexane as eluent. The title compound was obtained as a yellow solid, mp: 146-150° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][NH:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[C:9]([Cl:16])[N:8]=1)[CH3:2].C(N(CC)CC)C.[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>O1CCCC1.[Pt](=O)=O>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:30](=[O:31])[C:29]2[CH:33]=[CH:34][C:26]([Cl:25])=[CH:27][CH:28]=2)=[CH:11][CH:10]=[C:9]([Cl:16])[N:8]=1)[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)CNc1nc(Cl)ccc1[N+](=O)[O-]
Agent: O=[Pt]=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CNc1nc(Cl)ccc1NC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 31 %

Procedure:
A solution of N-(6-chloro-3-nitro-2-pyridinyl) glycine ethyl ester (5.0 g, 0.0193 mole) in tetrahydrofuran (100 ml) was hydrogenated over platinum dioxide (0.5 g) at room temperature. After 2/3 of the theoretical amount of hydrogen had been absorbed, the mixture was filtered and a fresh portion of platinum dioxide (0.5 g) was added. The hydrogenation was continued until the theoretical amount of hydrogen was absorbed. The reaction mixture was cooled in ice, dried over magnesium sulfate and filtered. Triethylamine (2.05 g, 0.0203 mole) and 4-chlorobenzoyl chloride (3.55 g, 0.0203 mole) were added simultaneously, dropwise, to the cooled and stirred solution. After stirring at room temperature for 1.75 hours, the mixture was evaporated under reduced pressure and partitioned between water (100 ml) and ethyl acetate (100 ml). The layers were separated and the aqueous layer was re-extracted with ethyl acetate. The combined ethyl acetate layers were washed three times with saturated sodium chloride solution, dried over magnesium sulfate, charcoaled, filtered, and evaporated under reduced pressure. The resulting solid was dissolved in hot isopropyl alcohol, filtered hot and cooled to room temperature to give a solid which was collected by filtration and rinsed with isopropyl ether to give 2.2 g of title compound (31% yield). A 0.5 g portion was dissolved in hot isopropyl alcohol, filtered hot, isopropyl ether was added, and the mixture was cooled. The resulting suspension was filtered, the filtrate was evaporated under reduced pressure, and the residue was recrystallized from isopropyl alcohol/water and dried under high vacuum at 60° C. to give 0.37 g of the title compound, mp 157°-158.5° C.
Reaction SMILES: [C:1]12([C:11]([OH:13])=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(Cl)(=O)C>CO>[CH3:1][C:11]([OH:13])=[O:12].[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Solvent: CC(=O)Cl
Solvent: CO
Product: C1C2CC3CC1CC(C2)C3
Product: CC(=O)O
Yield: 97 %

Procedure:
Stir 1.0 mol of adamantane carboxylic acid in 600 ml of methanol. Under ice cooling, drop 1.53 mol of acetyl chloride into the solution within 1 h. Remove the ice bath, and allow the reaction mixture to reach room temperature. Subsequently, heat for 3 hrs under reflux. Evaporate the reaction mixture to dryness under vacuum and distill. (Yield: 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:20][CH2:21][CH2:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[C:17]([OH:19])=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:33](O)[CH3:34]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:20][CH2:21][CH2:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[C:17]([O:19][CH2:33][CH3:34])=[O:18])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)C(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1

Procedure:
To a solution of 2.53 g (5.9 mmol) of 6-(p-chlorophenylsulfonamido)-2-[3-(3-pyridyl)propyl]-hexanoic acid in 150 ml ethanol is slowly added 1.5 ml (20.5 mmol) thionyl chloride and the reaction mixture is subjected to reflux for 8 h. The solvent is evaporated and the residue is adjusted to pH 8 using 1N aqueous sodium hydroxide solution. The mixture is then extracted with methylene chloride (2×50 ml). Combined organic extracts are dried (MgSO4) and evaporated to give an oil which is then purified by flash chromatography using ether as the eluent to obtain ethyl 6-(p-chlorophenylsulfonamido)-2-[3-(3-pyridyl)propyl]-hexanoate as an oil.
Reaction SMILES: O[C:2]1C=C[C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])/[C:13]/3=[CH:20]\[C:21]2[NH:22][CH:23]=[CH:24][CH:25]=2)=[CH:4][CH:3]=1.C(C1C=C2C(=CC=1)NC(=O)/C/2=C\C1NC=CC=1)#C.BrC1[S:46]C=CC=1.C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[NH:22]1[CH:23]=[CH:24][CH:25]=[C:21]1/[CH:20]=[C:13]1\[C:14](=[O:19])[NH:15][C:16]2[C:12]\1=[CH:11][C:10]([C:9]#[C:8][C:5]1[S:46][CH:2]=[CH:3][CH:4]=1)=[CH:18][CH:17]=2
Reactant: Brc1cccs1
Reactant: O=C1Nc2ccc(C#Cc3ccc(O)cc3)cc2/C1=C/c1ccc[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#Cc1ccc2c(c1)/C(=C/c1ccc[nH]1)C(=O)N2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(C#Cc3cccs3)cc2/C1=C/c1ccc[nH]1

Procedure:
This compound was also prepared in a manner analogous to the preparation of (Z)-1,3-dihydro-5-(4-hydroxyphenyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one in Example 83 above. In this example, (Z)-1,3-dihydro-5-ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (42 mg, 0.18 mmol) (from Example 82) was coupled with 2-bromothiophene (30 mg, 0.18 mmol) (Aldrich) using CuI (8 mg, 0.042 mmol) (Aldrich) and (Ph3P)2PdCl2 (14 mg, 0.020 mmol) (Aldrich) as catalyst in 1 mL DMF and 1 mL triethylamine at 70° C. for 14 hours to give (Z)-1,3-dihydro-3-[(1H-pyrrol-2-yl)-methylene]-5-(2-thiophenyl)ethynyl-2H-indol-2-one as a yellow powder. (Yield 25 mg, 44%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:20]C(C)=[CH:22][C:23]=2[C:24](O)=[O:25])/[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH2:28](Cl)[CH2:29]Cl.[CH:32]1[CH:33]=[CH:34][C:35]2[N:40](O)N=[N:38][C:36]=2C=1>CN(C=O)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:20][C:28]([CH3:29])=[CH:22][C:23]=2[C:24]([N:40]2[CH2:32][CH2:33][CH2:34][C@H:35]2[CH2:36][N:38]2[CH2:6][CH2:7][C@H:2]([F:1])[CH2:3]2)=[O:25])/[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)O)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Reactant: ClCCCl
Reactant: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2CCC[C@H]2CN2CC[C@H](F)C2)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.28 mmol), EDC (115 mg, 0.3 mmol), HOBt (40 mg, 0.3 mmol) in DMF (4 mL) was added TEA (0.14 mL) and (S)-3-fluoro-1-(S)-1-pyrrolidin-2-ylmethyl-pyrrolidine (100 mg, 0.58 mmol). The mixture was stirred at rt for 20 hours, The reaction was diluted with DCM, washed with water, NaHCO3, dried and concentrated. The residue was purified on a silica gel column to give the titled compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH:15]1([C:22]([OH:24])=[O:23])[CH2:18][CH:17]([C:19]([OH:21])=[O:20])[CH2:16]1.O>CN(C=O)C>[C@H:15]1([C:22]([O:24][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:23])[CH2:18][C@@H:17]([C:19]([O:21][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:20])[CH2:16]1.[C@H:15]1([C:22]([O:24][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:23])[CH2:18][C@H:17]([C:19]([O:21][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:20])[CH2:16]1
Reactant: BrCc1ccccc1
Reactant: O=C(O)C1CC(C(=O)O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)[C@H]1C[C@@H](C(=O)OCc2ccccc2)C1
Product: O=C(OCc1ccccc1)[C@H]1C[C@H](C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.6 %

Procedure:
Potassium carbonate (575 mg, 4.16 mmol) and benzyl bromide (0.495 mL, 4.16 mmol) were added to a solution of cyclobutane-1,3-dicarboxylic acid (cis-trans mixture) (200 mg, 1.39 mmol) in DMF (4.0 mL) at room temperature, and the mixture was stirred overnight at room temperature. To the reaction mixture was added water at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 0→5% ethyl acetate/hexane) to give dibenzyl cis-cyclobutane-1,3-dicarboxylate (106.3 mg, 0.328 mmol, 23.6%) as a less polar compound, and dibenzyl trans-cyclobutane-1,3-dicarboxylate (103.1 mg, 0.318 mmol, 22.9%) as a more polar compound, respectively. NMR spectrum of dibenzyl cis-cyclobutane-1,3-dicarboxylate
Reaction SMILES: [F:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]1=[O:12].N1C=CC=CC=1.[CH3:24][O:25][C:26]1[C:27]([O:46][CH3:47])=[C:28]([CH:43]=[CH:44][CH:45]=1)[C:29](Cl)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C)C1C=CN=CC=1.CO>[CH3:24][O:25][C:26]1[C:27]([O:46][CH3:47])=[C:28]([CH:43]=[CH:44][CH:45]=1)[C:29]([O:9][CH2:8][C@H:5]1[O:4][C@@H:3]([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[C@H:2]([F:1])[C@@H:6]1[OH:7])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2F)c(=O)[nH]1
Reactant: COc1cccc(C(Cl)(c2ccccc2)c2ccccc2)c1OC
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: c1ccncc1
Product: COc1cccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](F)[C@@H]2O)(c2ccccc2)c2ccccc2)c1OC
Reaction time: 3 h

Procedure:
0.5 g (about 2 mmol) of 2′-fluoro-2′-deoxyuridine is coevaporated with 10 ml of abs. pyridine twice in a 50 ml Schlenk flask. The dried nucleoside is taken up in 25 ml of abs. pyridine and, at room temperature, 0.66 g (about 2.2 mmol) of dimethoxytrityl chloride and 10 mg of 4-dimethylaminopyridine are added. After three hours, 1 ml of methanol was added to the mixture, which was then evaporated to dryness in vacuo. The remaining oil is taken up in 50 ml of methylene chloride (deacidified over aluminum oxide) and extracted three times with 50 ml of water. The organic phase is dried over sodium sulfate. After the methylene chloride had been stripped off, the crude product remained as a solid foam. To remove more highly tritylated components and the tritanol, the crude product was digested with 30 ml of abs. benzene at 40-50° C.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[F:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.Cl[C:17]1[N:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]>O>[F:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][C:17]1[N:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]
Reactant: O=C(O)c1cccnc1Cl
Reactant: Oc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cccnc1Oc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 19.2 %

Procedure:
Sodium hydride dispersion, 50% by weight (3.05 grams, 63.47 mmol) is placed into a 125 ml round bottom equipped with a stir bar and condenser under nitrogen and is charged with 32 ml of dimethylformamide. 3-Fluorophenol (3.56 grams, 31.73 mmol) is added portionwise over five minutes. During this addition, an exotherm and vigorous gas evolution is observed. The reaction is allowed to stir for five minutes. 2-Chloronicotinic acid (5.00 grams, 31.73 mmol) is added portionwise over five minutes. Gas evolution is observed. When it subsides, the reaction is heated to reflux for 2 hours. The reaction is cooled to room temperature and 300 ml of water is added. The aqueous layer is extracted with diethyl ether (2×200 ml). The aqueous layer is then pH adjusted to acidic with glacial acetic acid and extracted with ethyl acetate (3×150 ml). The organics are combined and washed with water (2×150 ml). The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield a yellow oil. The oil is purified by trituration with diethyl ether/hexanes (3/1) to yield 1.42 grams (19.2%) of product as a yellow crystalline solid.
Reaction SMILES: [CH2:1]([C@@:8]12[CH2:20][CH2:19][CH2:18][N:9]1[C@@H](C(Cl)(Cl)Cl)[O:11][C:12]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:21]>CO>[CH2:1]([C@@:8]1([C:12]([NH2:21])=[O:11])[CH2:20][CH2:19][CH2:18][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@]12Cc1ccccc1
Reactant: N
Solvent: CO
Product: NC(=O)[C@]1(Cc2ccccc2)CCCN1
Temperature: 50 °C

Procedure:
A mixture of (3R,7aR)-7a-benzyl-3-trichloromethyl-tetrahydro-pyrrolo[1,2-c]oxazol-1one (1.40 g, prepared as described by Wang and Germanas Synlett 1999, 33-36.) and 7 M ammonia in MeOH (15 ml) was heated at 50° C. for 3 days in a sealed vessel. The cooled RM was then evaporated and triturated with chloroform to give the title compound as a white solid.