Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1.[C:14]1(=[O:24])[O:19][C:17](=[O:18])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12>C(Cl)(Cl)Cl>[C:17]([C:16]1[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=1[C:14]([NH:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1)=[O:24])([OH:19])=[O:18]
Reactant: NCCSc1cccc2nccn12
Reactant: O=C1OC(=O)c2ccccc21
Solvent: ClC(Cl)Cl
Product: O=C(O)c1ccccc1C(=O)NCCSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 14 h
Yield: 0.1 %

Procedure:
To a solution of 5-[2-(amino)ethylthio]imidazo[1,2-a]pyridine (1.12 g, 5.8 moles) in chloroform (58 ml) was added phthalic anhydride (1.12 g, 7.56 moles) and the mixture was stirred at room temperature for 14 hours and then heated at reflux for 5 hours. The reaction mixture was cooled by standing. The crystals precipitated were filtered off, washed with chloroform and dried to obtain 1.68 g of the desired product (84.8%, colorless crystals).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[O:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:20]([O:27][CH3:28])(=[O:26])[CH2:21][C:22]([O:24][CH3:25])=[O:23].N1CCNCC1.C(O)(=O)C>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:21]([C:20]([O:27][CH3:28])=[O:26])[C:22]([O:24][CH3:25])=[O:23])=[CH:5][C:4]=1[O:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc(C=O)cc1OCCc1ccccc1
Reactant: COC(=O)CC(=O)OC
Agent: C1CNCCN1
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: COC(=O)C(=Cc1ccc(OC)c(OCCc2ccccc2)c1)C(=O)OC
Temperature: 25 °C
Yield: 90.6 %

Procedure:
4-Methoxy-3-(2-phenylethoxy)benzaldehyde (51.26 g), dimethyl malonate (26.43 g), piperazine (1.70 g) and acetic acid (1.20 g) were refluxed by heating in 300 ml of benzene under azeotropic dehydration conditions for 8 hours. After the reaction solution was cooled to room temperature, it was washed with water, 1 N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of NaCl in consecutive order and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration and the filtrate was concentrated under reduced pressure. The residue was recrystallized from isopropyl ether-dichloromethane to obtain 67.15 g of methyl 3-[4-methoxy-3-(2-phenylethoxy)phenyl]-2-methoxycarbonylacrylate.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27](O)=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:50][C@@H:51]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH3:52].Cl>CN(C=O)C.C(Cl)CCl>[C:56]([O:55][C:53](=[O:54])[C@H:51]([NH:50][C:27]([C:18]1[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@H:8]2[C:6](=[O:7])[NH:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[O:30])[N:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:19]=1)=[O:28])[CH3:52])([CH3:59])([CH3:58])[CH3:57]
Reactant: C[C@@H](N)C(=O)OC(C)(C)C
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: C[C@@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)OC(C)(C)C
Reaction time: 12 h

Procedure:
To a solution of 500 mg 5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 5 ml DMF were added 186 mg HOBt, 232 mg EDC, 0.50 ml DIPEA and 220 mg D-Ala-OtBu×HCl. After stirring for 12 h it was concentrated and the residue dissolved in ethyl acetate. It was extracted with aqueous LiCl (4% w/w), aqueous NaHCO3 and 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated to furnish the crude coupling product as colorless oil.
Reaction SMILES: Cl.[SH:2][CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[N:20]([CH3:21])[C:19]3[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:18]=3[N:17]=2)=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5].N1C=CC=CC=1.[O:34]1CC[CH2:36][CH2:35]1.C(OC(=O)C)(=O)C>CN(C)C=O>[C:35]([S:2][CH:3]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]2[N:20]([CH3:21])[C:19]3[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:18]=3[N:17]=2)=[CH:12][CH:13]=1)[C:4]([OH:6])=[O:5])(=[O:34])[CH3:36]
Reactant: COc1ccc2nc(COc3ccc(CC(S)C(=O)O)cc3)n(C)c2c1
Reactant: C1CCOC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc2nc(COc3ccc(CC(SC(C)=O)C(=O)O)cc3)n(C)c2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 2-mercapto-3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]propionic acid hydrochloride (1.5 g), pyridine (0.87 g), tetrahydrofuran (30 ml) and N,N-dimethylformamide (30 ml) was added acetic anhydride (0.56 g). The mixture was stirred at room temperature for 5 hours and allowed to stand for 36 hours and then concentrated. The residual insoluble material was collected by filtration and washed with ethyl acetate to afford the title compound (1.55 g, mp 209-214° C., pale yellow powder).
Reaction SMILES: Cl.O1CCOCC1.[CH2:8]([C@H:10]([NH:17][C:18](=[O:32])[C:19]([CH2:30][CH3:31])([CH2:28][CH3:29])[NH:20][C:21]([O:23]C(C)(C)C)=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:9].C(N(CC)CC)C.C([CH:47]([C:63]([O-:65])=[O:64])[C@@H:48](C([O-])=O)[NH:49]C(OCC1C=CC=CC=1)=O)C1C=CC=CC=1.O.C1C=CC2N(O)N=NC=2C=1>>[CH2:8]([C@H:10]([NH:17][C:18](=[O:32])[C:19]([CH2:28][CH3:29])([CH2:30][CH3:31])[NH:20][C:21](=[O:23])[C@H:48]([CH2:47][C:63](=[O:64])[OH:65])[NH2:49])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:9]
Reactant: O=C(N[C@H](C(=O)[O-])C(Cc1ccccc1)C(=O)[O-])OCc1ccccc1
Reactant: CC[C@H](NC(=O)C(CC)(CC)NC(=O)OC(C)(C)C)c1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC[C@H](NC(=O)C(CC)(CC)NC(=O)[C@@H](N)CC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.3 %

Procedure:
19 ml of 4N-HCl/dioxane solution were added to 1.31 g (3.76 mmols) of N-t-butoxycarbonyl-α,α-diethylglycine (S)-α-ethylbenzylamide, and the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure, 30 ml of ether was added to the residue, and this was again concentrated. The residue was dissolved in 25 ml of methylene chloride, and 0.55 ml (4.13 mmols) of triethylamine and 1.48 g (4.13 mmols) of β-benzyl-N-benzyloxycarbonyl-L-aspartate were added thereto. Under cooling, 0.79 g (4.13 mmols) of water-soluble carbodiimide hydrochloride and 0.51 g (3.76 mmols) of HOBt were added thereto, and these were stirred for one hour under cooling and then overnight at room temperature. The reaction mixture was concentrated under reduced pressure and 50 ml of aqueous 5% citric acid were added. The resulting residue was extracted two times each with 50 ml of ethyl acetate and then washed with 20 ml of water, 25 ml of aqueous 5% sodium hydrogencarbonate and 20 ml of brine, in that order. The resulting organic layer was dried with anhydrous magnesium sulfate and filtered, and the resulting filtrate was concentrated under reduced pressure. The residue was dissolved in 30 ml of methanol, 0.30 g of 10% Pd-carbon (water content 50) was added thereto, and the mixture was reduced under hydrogen. 40 ml of water was added to this, the catalyst was removed by filtration, and the resulting filtrate was concentrated to about 1/4. This was then stored in a refrigerator overnight. The crystal thus precipitated was removed by filtration and dried to obtain 0.40 g (1.10 mmols) of α-L-aspartyl-α,α-diethylglycine (S)-α-ethylbenzylamide.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:22]([O:24]CC)=O)[N:6]2C.Cl.[NH2:28][C:29]([NH2:31])=[NH:30].[CH3:32][O-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:22]([N:30]=[C:29]([NH2:31])[NH:28][CH3:32])=[O:24])[NH:6]2
Reactant: N=C(N)N
Reactant: CCOC(=O)c1cc2c(Cl)cc(Oc3ccc([N+](=O)[O-])cc3)cc2n1C
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNC(N)=NC(=O)c1cc2c(Cl)cc(Oc3ccc([N+](=O)[O-])cc3)cc2[nH]1
Yield: 46.9 %

Procedure:
The reaction was carried out in a manner similar to Example 186 b) except for using 0.45 g (1.32 mmol) of ethyl 4-chloro-1-methyl-6-(4-nitrophenoxy)-2-indolecarboxylate, 2.52 g (26.4 mmol) of guanidine hydrochloride, 1.42 g (26.4 mmol) of sodium methoxide and 25 ml of methanol. Thus, 0.24 g (47.0%) of 4-chloro-1-methyl-6-(4-nitrophenoxy)-2-indoloylguanidine was obtained.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[N:17]=[C:16]([C:18]2[S:22][C:21]([NH:23][C:24](=[O:26])[CH3:25])=[N:20][C:19]=2[CH3:27])[CH:15]=[CH:14][CH:13]=1.CCCC(C)C>N1C=CC=CC=1>[CH3:27][C:19]1[N:20]=[C:21]([NH:23][C:24](=[O:26])[CH3:25])[S:22][C:18]=1[C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:11][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[N:17]=1
Reactant: CC(=O)Nc1nc(C)c(-c2cccc(N)n2)s1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CCCC(C)C
Product: CC(=O)Nc1nc(C)c(-c2cccc(NS(=O)(=O)c3ccccc3)n2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Benzenesulfonyl chloride (0.77 mL) was added to a stirred mixture of N-[5-(6-aminopyridin-2-yl)-4-methyl-1,3-thiazol-2-yl]acetamide (249 mg) and pyridine (10 mL) and the reaction mixture was stirred at room temperature for 30 minutes. The resultant mixture was poured into isohexane (400 mL). The supernatant liquid was decanted from a residual gum. A 7M methanolic ammonia solution (20 mL) was added to the residual gum and the mixture was stirred at room temperature for 1 hour. The resultant mixture was evaporated and the residue was purified by preparative HPLC. There was thus obtained the title compound (296 mg); 1H NMR Spectrum: (DMSO-d6) 2.18 (s, 3H), 2.44 (s, 3H), 6.83 (d, 1H), 7.20 (d, 1H), 7.62 (m, 3H), 7.70 (t, 1H), 8.03 (d, 2H), 11.17 (br s, 1H), 12.12 (s, 1H); Mass Spectrum: M+H+ 389.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].C[C:20]([N:22]([CH3:24])[CH3:23])=O>CN(C=O)C>[CH3:20][N:22]([CH3:24])/[CH:23]=[CH:1]/[C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CC(=O)N(C)C
Reactant: CCOC(=O)c1cc(C)c([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(/C=C/N(C)C)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 32.3 %

Procedure:
A mixture of ethyl 5-methyl-2,4-dinitrobenzoate (39 g, 0.15 mol) and DMA (32 g, 0.27 mol) in DMF (200 mL) was heated at 100° C. for 5 h. The mixture was poured into ice water and the precipitated solid was filtered and washed with water to afford (E)-ethyl 5-(2-(dimethylamino)vinyl)-2,4-dinitrobenzoate (15 g, 28%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3([C:21]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[O:22])[CH2:20][CH2:19]3)=[O:17])=[C:11]([F:31])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH2:32]([N:34]([CH2:37][CH3:38])[CH2:35]C)C.ClC(OC1C=CC=CC=1)=[O:41].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[N:34]1([C:32]([NH:1][C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]4([C:21]([NH:23][C:24]5[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=5)=[O:22])[CH2:20][CH2:19]4)=[O:17])=[C:11]([F:31])[CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[O:41])[CH2:35][CH2:38][CH2:37]1
Reactant: CCN(CC)CC
Reactant: Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1)N1CCC1
Reaction time: 0.5 h
Yield: 72 %

Procedure:
N-{4-[(2-Aminopyridin-4-yl)oxy]-2-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (1.5 g) was dissolved in tetrahydrofuran (15 ml) under a nitrogen atmosphere, and triethylamine (0.987 ml) and phenyl chloroformate (0.978 ml) were added dropwise at room temperature in this order, followed by stirring for 30 min. The reaction mixture was stirred after addition of ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was separated, washed with brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (7.5 ml). Triethylamine (4.92 ml) and azetidine hydrochloride (1.33 g) were added at room temperature, followed by stirring for 7.5 hr. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with water (three times) and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. To the resultant residue were added ethyl acetate (5 ml) and heptane (5 ml) to precipitate a solid. The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (1.29 g, 72%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4](Cl)[N:3]=1.[CH3:19][NH2:20].[OH-].[Na+]>>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4]([NH:20][CH3:19])[N:3]=1
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Reactant: CN
Agent: [Na+]
Agent: [OH-]
Product: CNc1nc(N)nc2c1ncn2[C@H]1C=C[C@@H](CO)C1
Yield: 70 %

Procedure:
(±)-cis-4-(2-Amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol (0.400 g, 1.5 mmol) from Example 4 and methylamine (40% aqueous solution, 25 mL) were stirred at 60° C. for 0.5 hours. The solution was allowed to cool to room temperature before the addition of 1.5 mL of 1.5 N NaOH. Evaporation left the crude product which was purified by elution from a silica gel column with 5% methanolchloroform. The resulting solid was slurried in acetonitrile to yield a pale yellow powder (0.274 g, 70%); m.p. 221-223° C.
Reaction SMILES: [CH3:1][C:2](=[CH2:6])[C:3](O)=[O:4].S(Cl)(Cl)=O.[C:11]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[C:20]([F:23])([F:22])[F:21])#[N:12]>CC(N(C)C)=O>[CH3:1][C:2](=[CH2:6])[C:3]([NH:17][C:16]1[CH:18]=[CH:19][C:13]([C:11]#[N:12])=[C:14]([C:20]([F:21])([F:22])[F:23])[CH:15]=1)=[O:4]
Reactant: C=C(C)C(=O)O
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: C=C(C)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
Methyl acrylic acid (510 mg, 6 mmol) in DMA (10 ml) was treated with thionyl chloride (714 mg, 6 mmol) at 0° C. The mixture was stirred for 30 min then 4-cyano-3-trifluoromethyl-aniline (1.0 g, 6.0 mmol) was added. The resulting suspension was stirred overnight and then quenched with NaHCO3. The reaction mixture was extracted with ethyl acetate, washed with brine and dried with Na2SO4. The resulting concentrated crude product was purified on column (Ethyl acetate:Hexane, 1:2) to yield the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[O:12].O1C2=CC3C(=O)C(=O)NC=3C=C2OCC1.Br[CH:29]([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.BrCC1OC(C(F)(F)F)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:8](=[O:11])[C:7]2=[O:12]
Reactant: O=C1Nc2c(F)cccc2C1=O
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: FC(F)(F)c1ccc(CBr)o1
Agent: O=C1Nc2cc3c(cc2C1=O)OCCO3
Product: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2c(F)cccc21

Procedure:
Following the procedure as described in PREPARATION 26A and making non-critical variations using 7-fluoroisatin to replace 2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione, and bromodiphenylmethane to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 7-fluoro-1-(diphenylmethyl)-1H-indole-2,3-dione was obtained (80%): MS (ES+) m/z 353.7 (M+23).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)[CH:15]=[C:14]([C:25]([OH:27])=O)[CH:13]=1.Cl.[O:29]1[CH2:34][CH2:33][N:32]([CH2:35][C@@H:36]([NH2:38])[CH3:37])[CH2:31][CH2:30]1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O>>[CH3:37][C@@H:36]([NH:38][C:25]([C:14]1[CH:13]=[C:12]([C:3]2[C:4]([C:8]([F:9])([F:10])[F:11])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)[CH:15]=1)=[O:27])[CH2:35][N:32]1[CH2:33][CH2:34][O:29][CH2:30][CH2:31]1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-c3c(F)cccc3C(F)(F)F)c2)nc1
Reactant: C[C@H](N)CN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)CN3CCOCC3)cc(-c3c(F)cccc3C(F)(F)F)c2)nc1
Temperature: 25 °C

Procedure:
A round bottom flask was charged with 2′-fluoro-5-(5-methylpyridin-2-yl)-6′-(trifluoromethyl)biphenyl-3-carboxylic acid (100.00 mg, 0.26644 mmol), (S)-1-morpholinopropan-2-amine hydrochloride (112.10 mg, 0.62047 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.49150 g, 1.2926 mmol), N,N-diisopropylethylamine (0.36025 mL, 2.0682 mmol), N,N-dimethylformamide (0.882 mL, 11.4 mmol) and the reaction stirred over night at room temperature. The solvent was removed under reduced pressure and the residue purified by prep HPLC to get the compound as white solid.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:21]=[C:19]([OH:20])[C:17]([OH:18])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([N+]([CH2:35][CH2:36][CH2:37][CH3:38])(CCCC)CCCC)CCC.[C:39](N[C@@H](CC1C=C(O)C(O)=CC=1)C(O)=O)([O:41][C:42](C)([CH3:44])[CH3:43])=[O:40].C(=O)(O)[O-].CN1CC[CH2:67][C:66]1=O>C(OC)(C)(C)C>[OH:20][C:19]1[CH:21]=[C:14]([CH2:13][C@H:9]([NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])[C:10]([O:12][CH2:43][C@H:42]([O:41][C:39]([C:38]2[CH:37]=[CH:36][CH:35]=[CH:67][CH:66]=2)=[O:40])[CH3:44])=[O:11])[CH:15]=[CH:16][C:17]=1[OH:18]
Reactant: CN1CCCC1=O
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Agent: O=C([O-])O
Solvent: COC(C)(C)C
Product: C[C@H](COC(=O)[C@H](Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C)OC(=O)c1ccccc1
Temperature: 100 °C

Procedure:
Boc-Dopa TBA salt 3 (50 g, 93 mmol), bicarbonate-washed (1R)-2-chloroisopropyl benzoate 5 (20 g, 100 mmol), and N-methylpyrrolidinone (NMP) (100 mL) were added to a 250 mL round bottom flask. The mixture was stirred under a nitrogen atmosphere and heated in an oil bath at 100° C. After ca. 72 hrs the reaction was cooled to room temperature, diluted with tert-butyl methylether (MTBE) (1 L), and washed twice with deionized water (2 L, then 1 L). The organic phase was separated, dried over anhydrous sodium sulfate (Na2SO4), filtered, and concentrated under reduced pressure to provide 35 g (76 mmol) of (2R)-2-phenylcarbonyloxypropyl(2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate 6 as a tan, viscous oil.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19].[C:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)#[N:21]>>[C:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[NH:4][C:3]2=[O:19])=[O:27])=[CH:24][CH:23]=1)#[N:21]
Reactant: NC1N=C(c2ccccc2)c2ccccc2NC1=O
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Product: N#Cc1ccc(C(=O)NC2N=C(c3ccccc3)c3ccccc3NC2=O)cc1

Procedure:
The procedure of Example 134 was carried out employing equivalent amounts of 1,3-dihydro-3-(RS)-amino-5-phenyl-2H-1,4-benzodiazepin-2-one and 4-cyanobenzoylchloride. The product was purified by chromatography on silica gel (5% (v/v) Et2O in CH2Cl2 elution). The combined product fractions were evaporated to dryness in vacuo and crystallized to give the title compound which was dried at 65° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH:4]=[CH:5][CH2:6]2.C([Li])CCC.CCCCCC.Cl[P:24]([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26].Cl[Sn:32]([CH2:41][CH2:42][CH2:43][CH3:44])([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36]>CCOCC>[CH:25]([P:24]([C:5]1[CH:4]([Sn:32]([CH2:37][CH2:38][CH2:39][CH3:40])([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:33][CH2:34][CH2:35][CH3:36])[C:3]2[C:7]([CH:6]=1)=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=2[CH3:1])[CH:28]([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(C)P(Cl)C(C)C
Reactant: Cc1ccc(C)c2c1C=CC2
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)C1C(P(C(C)C)C(C)C)=Cc2c(C)ccc(C)c21
Temperature: -20 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
100 ml of ether were placed in a round-bottomed flask containing 5.0 g (0.035 moles) of 4,7-dimethylindene (compound 21); the solution was cooled to −20° C. 14 ml of a 2.5 molar solution of butyllithium in hexane (0.035 moles) were added over 5 min to form a yellow solution. After removal of the cooling bath, the solution was heated to room temperature and subsequently stirred for 1 h. After cooling of the reaction mixture to −20° C., 5.3 g (0.035 moles) of chlorodiisopropylphosphine were added over 5 min to form a precipitate. The cooling bath was then removed and the reaction mixture was stirred for 1 h at room temperature. After cooling to −20° C., 14.0 ml of a 2.5 molar solution of butyllithium in hexane (0.035 moles) were added dropwise. When the addition was complete, the cooling bath was removed and the solution was heated slowly to room temperature and stirred for 1.5 h. After cooling of the suspension to 0° C., 11.4 g of chlorotributyltin (0.035 moles) were added dropwise. The suspension formed was heated to room temperature and stirred for 1.5 h. The ether was removed under vacuum, the crude product was dissolved in hexane again, the solution was filtered and the filtrate was concentrated under vacuum to leave 16 g (yield: 83%) of compound 22 in the form of a heavy yellow oil. 31P NMR (161.9 MHz, CD2Cl2): δ=−9 ppm.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([O-])=[O:23].[Na+]>CCOCC.O>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:22](=[O:23])[C:21]2[CH:25]=[CH:26][CH:27]=[C:19]([O:18][CH3:17])[CH:20]=2)=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: COc1cccc(C(=O)[O-])c1
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COc1cccc(C(=O)c2ccc(C(F)(F)F)cc2)c1
Reaction time: 64 h
Yield: 55 %

Procedure:
This is carried out under nitrogen at -60° C. 0.29 mol (65 g) of para-bromo-trifluoromethylbenzene dissolved in 100 ml of anhydrous ether is added dropwise to 0.29 mol of butyl-lithium in solution in ether (1.48 mol/liter). The reaction is followed by gas phase chromatography; when there is no longer any remaining para-bromo-trifluoromethylbenzene, 0.29 mol (50.5 g) of sodium 3-methoxybenzoate is added. The mixture is allowed to return to ambient temperature. After stirring for 64 hours, it is hydrolysed in iced water. The batch is extracted with ether. The ether phase is dried, decolorised and concentrated. 45 g of a product which has been recrystallised from a mixture of isopropyl ether and hexane are obtained. Melting point 69° C. Yield: 55%.