Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:44])[C@@H:15]([NH:25][C:26]([C:28]2[CH:32]=[C:31]([O:33][CH2:34][C:35](O)=[O:36])[N:30]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:29]=2)=[O:27])[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH2:65]([O:72][C:73](=[O:79])[C@@H:74]1[CH2:78][CH2:77][CH2:76][NH:75]1)[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1>CN(C=O)C.C(Cl)CCl>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:44])[C@@H:15]([NH:25][C:26]([C:28]2[CH:32]=[C:31]([O:33][CH2:34][C:35]([N:75]3[CH2:76][CH2:77][CH2:78][C@H:74]3[C:73]([O:72][CH2:65][C:66]3[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=3)=[O:79])=[O:36])[N:30]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:29]=2)=[O:27])[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)O)n(-c3ccccc3)n2)CC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)OCc3ccccc3)n(-c3ccccc3)n2)CC1
Reaction time: 12 h

Procedure:
To a solution of 2.50 g 4-{(S)-4-tert-butoxycarbonyl-2-[(5-carboxymethoxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid butyl ester in 30 ml DMF were added 621 mg HOBt, 1.3 ml DIPEA, 778 mg EDC and 981 mg L-proline benzyl ester hydrochloride. After stirring for 12 h the solvent was evaporated, the residue dissolved in ethyl acetate and subsequently extracted with aqueous LiCl (4% w/w) and aqueous NaHCO3. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The crude product thus obtained was used in the subsequent reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]([N:40]=[C:41]=[O:42])=[O:39])=[CH:33][CH:32]=1>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[F:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:37][C:38]([NH:40][C:41](=[O:42])[NH:1][C:2]2[CH:29]=[CH:28][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]4[CH2:17][CH2:18][CH:19]([CH2:22][N:23]5[CH2:27][CH2:26][CH2:25][CH2:24]5)[CH2:20][CH2:21]4)=[O:15])[CH:8]=3)=[CH:4][CH:3]=2)=[O:39])=[CH:35][CH:36]=1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(CN4CCCC4)CC3)c2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C(Cc1ccc(F)cc1)NC(=O)Nc1ccc(Oc2ccnc(NC(=O)N3CCC(CN4CCCC4)CC3)c2)cc1
Reaction time: 17 h
Yield: 63.1 %

Procedure:
To a solution of 4-(pyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid [4-(4-aminophenoxy)pyridin-2-yl]amide (50 mg) in N,N-dimethylformamide (1.5 ml) was added a solution of 0.25 M 2-(4-fluorophenyl)acetyl isocyanate in ethyl acetate (1.51 ml) under a nitrogen atmosphere, followed by stirring for 17 hrs. The reaction mixture was partitioned between ethyl acetate (100 ml) and a saturated aqueous solution of sodium hydrogencarbonate (50 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (50 ml), water (50 ml), brine (50 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate). Fractions containing the target compound were concentrated to give a residue, which was then suspended in ethyl acetate (1.5 ml) and hexane (1.5 ml). The solid was filtered off and dried under aeration to provide the titled compound (45.7 mg, 63.1%) as white powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]=2[CH3:19])[O:3]1.C1C(=O)N([Br:28])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:28][CH2:19][C:10]1[CH:11]=[CH:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]=1[B:4]1[O:3][C:2]([CH3:20])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]1
Reactant: Cc1ccc2ccccc2c1B1OC(C)(C)C(C)(C)O1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)OB(c2c(CBr)ccc3ccccc23)OC1(C)C
Temperature: 75 °C
Reaction time: 14 h
Yield: 101.8 %

Procedure:
A mixture of 47.3 g (176 mmol) of 4,4,5,5-tetramethyl-2-(2-methyl-1-naphthyl)-1,3,2-dioxaborolane, 33.0 g (185 mmol) of NBS, and 0.17 g (0.70 mmol) of benzoyl peroxide in 340 ml of CCl4 was stirred in argon atmosphere for 14 h at 75° C. The resulting mixture was cooled to room temperature, filtered through a glass frit (G3), and the filtrate was evaporated to dryness. This procedure gave 62.2 g (99%) of a beige solid. Anal. calc. for C17H20BBrO2: C, 58.83; H, 5.81. Found: C, 58.75; H, 5.90. 1H NMR (CDCl3): δ 8.30 (m, 1H, 8-H), 7.84 (d, J=8.3 Hz, 1H, 4-H), 7.79 (m, 1H, 5-H), 7.43-7.52 (m, 3H, 3,6,7-H), 4.96 (s, 2H, CH2Br), 1.51 (s, 12H, CMe2CMe2).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(N(CC)CC)C.[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=1[N+:28]([O-:30])=[O:29]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[CH:23][C:22]=1[N+:28]([O-:30])=[O:29]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(Nc2ccc(F)c([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A round bottom flask is charged with 3-nitrophenylboronic acid (4.2 g, 25 mmol), dry molecular sieves (5 g), copper acetate (1.95 g, 12.5 mmol) and dry dichloromethane (150 mL). Triethylamine (8.7 mL, 62.5 mmol) is added followed by the addition of 4-fluoro-3-nitroaniline (2.27 g, 12.5 mmol). The resulting mixture is stirred at ambient temperature for three days. The mixture is filtered through celite and washed with EtOAc. The filtrate is concentrated and purified by column chromatography (EtOAc/Hexane=1:3) to give the desired product: 1H NMR (400 MHz, DMSO) δ 9.12 (s, 1 H), 7.82 (m, 1 H), 7.79-7.37 (m, 1 H), 7.73-7.70 (m, 1 H), 7.56-7.49 (m, 4 H); LC-MS: 278.3 (MH+).
Reaction SMILES: [Li+].[OH-].[CH2:3]([C@H:7]1[CH2:11][CH2:10][N:9]([C@@H:12]([CH2:17][CH:18]=[CH2:19])[C:13]([O:15]C)=[O:14])[C:8]1=[O:20])[CH2:4][CH2:5][CH3:6].Cl>O.C1COCC1>[CH2:3]([C@H:7]1[CH2:11][CH2:10][N:9]([C@@H:12]([CH2:17][CH:18]=[CH2:19])[C:13]([OH:15])=[O:14])[C:8]1=[O:20])[CH2:4][CH2:5][CH3:6]
Reactant: C=CC[C@@H](C(=O)OC)N1CC[C@H](CCCC)C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CC[C@@H](C(=O)O)N1CC[C@H](CCCC)C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.2 %

Procedure:
Step B (5): A solution of LiOH (2 M, 69 mg, 2.9 mmol) in 1.4 mL of H2O was added to diastereomer A, (S)-methyl 2-((S)-3-butyl-2-oxopyrrolidin-1-yl)pent-4-enoate, (242 mg, 0.96 mmol) from Step B (4) in THF (1.4 mL). The reaction mixture was stirred at room temperature for 3 days. The mixture was poured into 1 N HCl and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO4 and concentrated in vacuo to give 182 mg of (S)-2-((S)-3-butyl-2-oxopyrrolidin-1-yl)pent-4-enoic acid as colorless oil: LC-MS (M+H)+=240.2; 1H NMR (500 MHz, CDCl3) δ 5.60-5.82 (m, 1H), 5.03-5.21 (m, 2H), 4.74 (dd, J=10.68, 4.88 Hz, 1H), 3.38-3.48 (m, 1H), 3.29-3.38 (m, 1H), 2.70-2.81 (m, 1H), 2.51-2.62 (m, 1H), 2.36-2.49 (m, 1H), 2.11-2.25 (m, 1H), 1.79-1.91 (m, 1H), 1.66-1.79 (m, 1H), 1.23-1.43 (m, 5H), 0.80-0.96 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1.[C:23]1([CH2:29][CH2:30][CH2:31]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH2:31][CH2:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OCCCc3ccccc3)c(Cl)cc2F)c1=O

Procedure:
using 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione with 3-phenylpropyl bromide and sodium carbonate in dimethylformamide there is obtained 3-[4-chloro-2-fluoro-5-(3-phenylpropoxy)-phenyl]-1-methyl-6 -trifluoromethyl-2,4(1H,3H)-pyrimidinedione, 1H-NMR (CDCl3, 400 MHZ): 7.15°-7.34 ppm (m,6H), 6.71 ppm (d,1H), 6.36 ppm (s,1H), 3.96 ppm (t,2H), 3.55 ppm (d,3H), 2.83 ppm (t,2H), 2.10°-2.20 ppm (m,2H):
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([SH:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=O.C[O-].[Na+].[Cl:16][C:17]1[CH:18]=[C:19]([CH2:23][NH:24][C:25](=[O:28])[CH2:26]Cl)[CH:20]=[CH:21][CH:22]=1.C(O)(=O)C>CO.O>[OH:9][C:7]1[C:6]2[CH:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[S:12][C:26]=1[C:25]([NH:24][CH2:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[CH:18]=1)=[O:28]
Reactant: COC(=O)c1cc(Cl)ccc1S
Reactant: O=C(CCl)NCc1cccc(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: O=C(NCc1cccc(Cl)c1)c1sc2ccc(Cl)cc2c1O
Temperature: 25 °C
Yield: 90.3 %

Procedure:
To a solution of methyl 5-chloro-2-mercaptobenzoate (1.02 g; 0.005M) in 20 ml of methanol is added solid sodium methoxide (0.81 g; 0.015M; 3 eqv.) followed by N-[(3-chlorophenyl)methyl]chloroacetamide (1.10 g; 0.005M) and the mixture is refluxed under a nitrogen atmosphere for 30 minutes. The mixture is cooled to room temperature and added to a solution of 1.25 ml of glacial acetic acid in 20 ml of water and cooled to 0° C. The white solid is collected, washed with 50% methanol-water and air dried to give 1.60 g (91% yield) of the title compound; m.p. 184°-186° C.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[N:10]=[C:9]([C:19]([OH:21])=O)[CH2:8]2)=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>>[Br:1][C:2]1[S:6][C:5]([CH:7]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[N:10]=[C:9]([C:19]([Cl:24])=[O:21])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1=NN(c2ccccc2Cl)C(c2ccc(Br)s2)C1
Product: O=C(Cl)C1=NN(c2ccccc2Cl)C(c2ccc(Br)s2)C1
Reaction time: 2 h

Procedure:
5-(5-Bromo-thiophen-2-yl)-1-(2-chloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid (18.1 g, 46.9 mmol) prepared in Step 4 was added to thionyl chloride (200.0 mL). The reaction mixture was stitted at 100° C. for 2 hours and then concentrated under reduced pressure. The resulting residue was concentrated under reduced pressure three times, along with using toluene, to give 5-(5-bromo-thiophen-2-yl)-1-(2-chloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carbonyl chloride as a dark brown liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1F)[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][C:7]=1[F:14].Cl[C:20]1[CH:30]=[C:24]2[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]2[C:22](=[O:31])[N:21]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][O:13][C:20]2[CH:30]=[C:24]3[N:25]([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]3[C:22](=[O:31])[N:21]=2)=[CH:8][C:7]=1[F:14]
Reactant: OCc1ccc(Oc2ccc(F)c(Cl)c2)c(F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1ccc(Oc3cccc(Cl)c3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (4-(3-chloro-4-fluorophenoxy)-3-fluorophenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([F:17])([F:16])[CH2:6][NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:2].[Cl:19][C:20]1[N:25]=[C:24](Cl)[C:23]([N+:27]([O-:29])=[O:28])=[CH:22][N:21]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:18])[C:5]([F:17])([F:16])[CH2:6][N:7]([C:22]1[C:23]([N+:27]([O-:29])=[O:28])=[CH:24][N:25]=[C:20]([Cl:19])[N:21]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCOC(=O)C(F)(F)CNCCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)CN(CCc1ccccc1)c1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 17 h
Yield: 135.9 %

Procedure:
A solution of 0.57 g (0.0022 mole) of 2,2-difluoro-3-phenethylamino-propionic acid ethyl ester in 1 mL of ethyl acetate was added over 5 minutes to a cooled (0 degrees) mixture of 0.43 g (0.0022 mole) of 2,4-dichloro-5-nitro-pyrimidine, 0.75 g (0.0088 mole) of sodium bicarbonate and 6 mL of ethyl acetate. The cooling bath was removed and the mixture stirred for 17 hours at room temperature. Activated charcoal was added and after stirring briefly, the mixture was filtered through a pad of Celite, washing the filter pad with ethyl acetate. The filtrate was concentrated under reduced pressure to give 1.24 g of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-phenethyl-amino]-2,2-difluoro-propionic acid ethyl ester (IV-275) as a yellow thick oil. This material was used directly in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.I[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2cc[nH]c2c1
Reactant: Ic1ccccc1
Product: Fc1ccc2ccn(-c3ccccc3)c2c1

Procedure:
Prepared by Procedure, C and Scheme O using 6-fluoro-1H-indole and iodobenzene: ESMS m/e: 212.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[F:11])[C:4]([C:19]2[CH:20]=[C:21]([CH3:29])[C:22]([O:27][CH3:28])=[C:23]([CH:26]=2)[C:24]#[N:25])([C:12]2[CH:17]=[CH:16][CH:15]=[C:14](Br)[CH:13]=2)[N:3]=1.[N:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[N:32][CH:31]=1>>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[F:11])[C:4]([C:19]2[CH:20]=[C:21]([CH3:29])[C:22]([O:27][CH3:28])=[C:23]([CH:26]=2)[C:24]#[N:25])([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:34]3[CH:35]=[N:30][CH:31]=[N:32][CH:33]=3)[CH:13]=2)[N:3]=1
Reactant: OB(O)c1cncnc1
Reactant: COc1c(C)cc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)cc1C#N
Product: COc1c(C)cc(C2(c3cccc(-c4cncnc4)c3)N=C(N)c3c(F)cccc32)cc1C#N
Yield: 63 %

Procedure:
The title compound was synthesized as described for Example 1 in 63% yield, starting from 5-(3-amino-1-(3-bromophenyl)-4-fluoro-1H-isoindol-1-yl)-2-methoxy-3-methylbenzonitrile (88 mg, 0.20 mmol) and pyrimidin-5-ylboronic acid (36.3 mg, 0.29 mmol).
Reaction SMILES: B(Br)(Br)Br.[OH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:29])[CH2:13][C:14]([C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([O:25]C)=[C:18]([O:27]C)[CH:17]=1)=[O:15].C(O)C>C(Cl)Cl>[OH:27][C:18]1[CH:17]=[C:16]([C:14](=[O:15])[CH2:13][C:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[OH:5])=[O:29])[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]=1[OH:25]
Reactant: COc1cc(C(=O)CC(=O)c2ccccc2O)cc([N+](=O)[O-])c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCO
Product: O=C(CC(=O)c1ccccc1O)c1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
A solution of 1.82 g of boron tribromide in 20 ml of methylene chloride is added dropwise within about 20 minutes to a solution of 500 mg of 1-(o-hydroxyphenyl)-3-(3,4-dimethoxy-5-nitrophenyl)-1,3-propanedione in 50 ml of methylene chloride while stirring and under an argon atmosphere at -20°, whereupon the mixture is stirred at room temperature overnight. After cooling to -20° the mixture is treated dropwise with 25 ml of ethanol and evaporated at 40° in a water-jet vacuum. After recrystallization from ethanol, there is obtained 1-(3,4-dihydroxy-5-nitrophenyl)-3-(o-hydroxyphenyl)-1,3-propanedione in the form of yellow crystals of m.p. 251°-252°.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:24])[C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][C:16]=3[C:25](=[O:27])[NH2:26])[CH:7]=[CH:8][CH:9]=1.Br[CH2:31][C:32]([O:34][CH3:35])=[O:33]>CN(C=O)C.C(OCC)(=O)C>[F:29][C:2]([F:28])([F:1])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([O:24][CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][C:16]=3[C:25](=[O:27])[NH2:26])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)CBr
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(OC(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(OC(F)(F)F)c1
Reaction time: 0.05 h
Yield: 82.5 %

Procedure:
40% Methanolic Triton B (0.15 mL, 0.34 mM) was added to a solution of the 9-[(3-trifluoromethoxyphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (115 mg, 0.28 mM) in 8 mL DMF at room temperature. After 3 minutes, methyl bromoacetate (65 mg, 0.41 mM) was added and the resultant mixture stirred at room temperature for 23 hours. The mixture was diluted with ethyl acetate, washed with H2O, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 112 mg (83%) of the {9-[(3-trifluoromethoxyphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (DMSO-d6) δ7.6 (d, 1H, J=8 Hz), 7.55 (br s, 1H), 7.5-7.0 (m, 9H), 6.6 (d, 1H, J=8 Hz), 5.7 (s, 2H), 4.9 (s, 2H), and 3.75 (s, 3H). IR (KBr, cm−1) 3488, 3141, 1763, 1674, 1501, 1444, 1269, 1215, 1178, 1102, 772, and 714. MS (FD) m/e 472.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([C:21]3[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=3)[CH2:24][OH:25])[CH:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH2:9][S:10]2)=[CH:5][CH:4]=1>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([C:21]3[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=3)[CH:24]=[O:25])[CH:8]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[CH2:9][S:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2CSc3cc(OC)ccc3C2c2cccc(CO)c2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1ccc(C2CSc3cc(OC)ccc3C2c2cccc(C=O)c2)cc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
The mixture of 3-[7-methoxy-3-(4-methoxyphenyl)thiochroman-4-yl]benzyl alcohol (358 mg, 0.912 mmol) and manganese(IV) oxide (634 mg, 7.296 mmol) in methylene chloride (80 ml) was stirred at 40° C. for 3 h. When the reaction was completed, methylene chloride was added to the reaction mixture, which was then filtrated over silica gel and washed with several times with methylene chloride. The organic layer was concentrated under reduced pressure to give 360 mg (quant.) of the title compound as a white crystal.
Reaction SMILES: C([O:5][C:6](=[O:21])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:20][O:19][C:17]([CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][C:6]([OH:21])=[O:5])=[CH:10][CH:11]=1)=[O:18]
Reactant: COC(=O)COc1ccc(CCC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)COc1ccc(CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3-(4-Methoxycarbonylmethoxy-phenyl)-propionic acid tert-butyl ester (0.097 g, 0.33 mmol) is added a 90% solution of TFA in DCM (2 ml) and the resulting solution is stirred at room temperature for 1 hour. The solvents are removed in vacuo to yield 3-(4-Methoxycarbonylmethoxy-phenyl)-propionic acid as an off-white powder; [M+H-18]+ 256.0
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([C:7]#[N:8])[C:5]=1[C:12]#[N:13])([O-])=O.C(=O)([O-])[O-].[K+].[K+].N1[CH2:24][CH2:23][CH2:22][CH2:21]1>O>[N:1]1([C:4]2[CH:11]=[CH:10][CH:9]=[C:6]([C:7]#[N:8])[C:5]=2[C:12]#[N:13])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C1CCNC1
Reactant: N#Cc1cccc([N+](=O)[O-])c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: N#Cc1cccc(N2CCCC2)c1C#N
Yield: 56 %

Procedure:
A mixture of 3-nitrophthalonitrile (985 mg, 5.69 mmol), freshly dried potassium carbonate (3.0 g, 21 mmol) and pyrrolidine (15 mL) were heated at reflux for 4 h. The reaction mixture was poured into water (250 mL) to precipitate the product, and this was filtered off, washed with water, and dried to give 1 as an olive-brown powder (633 mg, 56%).
Reaction SMILES: [SH:1][C:2]1[N:6]=[C:5]([SH:7])[S:4][N:3]=1.[K].[K].[CH2:10]([Sn:14](Cl)(Cl)[CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH3:13]>C(O)C>[CH2:10]([Sn:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH3:13].[SH:1][C:2]1[N:6]=[C:5]([SH:7])[S:4][N:3]=1
Reactant: CCCC[Sn](Cl)(Cl)CCCC
Agent: Sc1nsc(S)n1
Agent: [K]
Solvent: CCO
Product: CCCC[Sn]CCCC

Procedure:
A solution of 5.9 g (0.026 m) of dipotassium 3,5-dimercapto-1,2,4-thiadiazole in 50 ml of ethanol was added slowly with agitation to an ethanol solution of 7.89 g (0.026 m) of dibutyltindichloride. The resulting reaction mixture was refluxed for 2 hours. A light yellow solid was isolated following several washes with ethanol and drying at 100° C. for 5 hours. Elemental analysis and other data of the product are recorded in Table III. The extreme pressure and antiwear characteristics of two base greases containing 5% of the solid product are listed in Table IV.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=1.O.[OH-].[Li+]>CO.O>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(CN2CCCCC2=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(CN2CCCCC2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
Methyl 4-[(2-oxopiperidino)methyl]benzoate (2.47 g, 10.0 mmol) obtained in Step 1 was dissolved in a mixed solvent of methanol (30 mL) and water (10 mL), and lithium hydroxide monohydrate (2.10 g, 50.0 mmol) was added thereto, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and 6 mol/L hydrochloric acid was added to the resulting residue to adjust the pH to 1, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure to afford 4-[(2-oxopiperidino)methyl]benzoic acid (629 mg. 27%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:45])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:44])[C@@H:33]([N:35](C)[C:36](=O)OC(C)(C)C)[CH3:34])[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:46]2[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:45])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:44])[C@@H:33]([NH:35][CH3:36])[CH3:34])[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:46]2[CH:47]=[CH:48][C:49]([CH3:52])=[CH:50][CH:51]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)c3)c3ccccc23)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](C)C(=O)Nc1cc(COc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)ccn1
Yield: 53.7 %

Procedure:
A solution of the carbamate (7) (25 mg, 0.04 mmol) in DCM/TFA (1:1 v/v, 2.0 mL) was stirred at RT for 30 min. The reaction mixture was evaporated in vacuo and the resulting residue was subjected to SCX capture and release and then purified by flash column chromatography (SiO2, 4 g, 0-100% EtOAc in MeOH, gradient elution) to afford the title compound (Example 9) as an off-white solid (13 mg, 57%): m/z 606 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.20 (3H, d), 1.27 (9H, s), 2.26 (3H, s), 2.39 (3H, s), 3.20 (1H, q), 5.38 (2H, s), 6.35 (1H, s), 7.01 (1H, d), 7.28 (1H, dd), 7.36 (2H, m), 7.44 (2H, m), 7.55-7.63 (3H, overlapping m), 7.93 (1H, m), 8.31 (1H, m), 8.34 (1H, dd), 8.36 (1H, br s), 8.60 (1H, s), 8.80 (1H, s).