Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:26])=[C:4]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[C:5]2[O:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH:36]=O)=[CH:28]1>CO.N1CCCCC1>[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](/[CH:36]=[C:8]2\[O:9][C:5]3[C:4]([CH2:12][N:13]4[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:15][CH2:14]4)=[C:3]([OH:26])[C:2]([Cl:1])=[CH:11][C:6]=3[C:7]\2=[O:10])=[CH:28]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)c(Cl)cc3c2OCC3=O)CC1
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)c(Cl)cc3c2O/C(=C\c2c[nH]c4ccccc24)C3=O)CC1
Temperature: 40 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
A solution of tert-butyl 4-[(5-chloro-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.014 g, 0.037 mmol) in methanol (2.0 mL) was added with 1H-indole-3-carboxaldehyde (0.013 g, 0.090 mmol). Then, the mixture was added with 5 drops of piperidine, and then the mixture was stirred at 40° C. for 2 hours. The reaction mixture was cooled to room temperature, and then the solid was collected by filtration, and washed with methanol to obtain tert-butyl (Z)-4-({2-[(1H-indol-3-yl)methylene]-5-chloro-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.016 g, 85%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[CH2:8][N:7]([C:13]3[N:17]([CH3:18])[N:16]=[C:15]([CH:19]4[CH2:21][CH2:20]4)[CH:14]=3)[CH2:6][CH2:5][C:4]=2[N:3]=1.[CH:22]([C:25]1[C:26](B2OC(C)(C)C(C)(C)O2)=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][N:29]=[CH:28]2)([CH3:24])[CH3:23].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.[Cl-].[Na+].O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:19]1([C:15]2[CH:14]=[C:13]([N:7]3[CH2:6][CH2:5][C:4]4[N:3]=[C:2]([C:26]5[C:25]([CH:22]([CH3:24])[CH3:23])=[CH:33][CH:32]=[C:31]6[C:27]=5[CH:28]=[N:29][NH:30]6)[CH:11]=[C:10]([CH3:12])[C:9]=4[CH2:8]3)[N:17]([CH3:18])[N:16]=2)[CH2:21][CH2:20]1
Reactant: Cc1cc(Cl)nc2c1CN(c1cc(C3CC3)nn1C)CC2
Reactant: CC(C)c1ccc2[nH]ncc2c1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2c(C(C)C)ccc3[nH]ncc23)nc2c1CN(c1cc(C3CC3)nn1C)CC2

Procedure:
Microwave was used to irradiated a solution of 2-chloro-6-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-4-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine (30 mg, 0.099 mmol), crude 5-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (38.2 mg, 0.119 mmol), Pd(PPh3)4 (11.45 mg, 9.91 μmol) and K3PO4 (42.1 mg, 0.198 mmol) in 1,4-dioxane (0.5 mL) and H2O (0.05 mL) at 130° C. for 1 h under nitrogen. Additional Pd(PPh3)4 (22.90 mg, 0.020 mmol) was added to the mixture. Microwave was irradiated to the mixture at 130° C. for further 2 h under nitrogen. The mixture was diluted with brine and EtOAc. The organic layer was separated, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on 12 g of silica gel (eluent: DCM/MeOH=100:0 to 10:1) to give 6-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-2-(5-isopropyl-1H-indazol-4-yl)-4-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine: 1H NMR (400 MHz, CDCl3) δ ppm 9.98 (br s, 1 H), 7.76 (d, J=0.76 Hz, 1H), 7.45-7.51 (m, 2 H), 7.12 (s, 1 H), 5.65 (s, 1 H), 4.11 (s, 2 H), 3.75 (s, 3 H), 3.30-3.33 (app t, 2 H), 3.15-3.24 (m, 3 H), 2.30 (s, 3 H), 1.87-1.94 (m, 1 H), 1.25 (d, J=7.07 Hz, 6 H), 0.89-0.94 (m, 2 H), 0.72-0.76 (m, 2 H); MS (ESI+) m/z 427.33 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([NH:12][C@@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]2)=[N:6][CH:7]=[C:8]([CH:10]=O)[CH:9]=1.[C:25]([O:28][CH2:29][CH3:30])([CH3:27])=[O:26].O>C1COCC1>[Cl:3][C:4]1[C:5]([NH:12][C@@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]2)=[N:6][CH:7]=[C:8](/[CH:10]=[CH:27]/[C:25]([O:28][CH2:29][CH3:30])=[O:26])[CH:9]=1
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ncc(C=O)cc2Cl)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)c(Cl)c1
Temperature: 15 °C

Procedure:
A solution of diethylphosphonoacetcacid ethyl ester (980 mg), in THF (5 ml) was added dropwise to admixture of 60% sodium hydride in oil (187 mg) in THF (30 mL) with stirring at 10-20° C. under atmospheric pressure of nitrogen, and the reaction mixture was stirred at ambient temperature for 30 minutes. A solution of tert-butyl (3R)-3-[(3-chloro-5-formyl-2-pyridinyl)amino]-1-pyrrolidinecarboxylate (0.95 g) in THF (10 ml) solution was added the above mixture and resultant mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-n-hexane (6:4). The eluted fractions containing the desired product were collected and evaporated in vacuo to give tert-butyl (3R)-3-({3-chloro-5-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-pyrrolidinecarboxylate (0.98 g)
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N+:12]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:9][C:8]([F:11])([F:10])[C:7]1[C:2]([C:19]2[CH:20]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=[CH:17][CH:18]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc(-c2ncccc2C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 7 h
Yield: 50.5 %

Procedure:
To a suspension of 2-chloro-3-trifluoromethylpyridine (908 mg), 3-nitrophenylboronic acid (1.09 g) and tetrakis(triphenylphosphine)-palladium (289 mg) in 1,2-dimethoxyethane (20 ml) was added 2M aqueous solution of sodium carbonate (6.5 ml). The mixture was stirred at 80° C. for 7 hours under a nitrogen atmosphere, then cooled to room temperature and diluted with ethyl acetate. The organic layer was separated, washed with water and brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 50 g, ethyl acetate:n-hexane=20:80 to 25:75) to give 3-(3-trifluoromethylpyridin-2-yl)-nitrobenzene (677 mg).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[O:16][CH:15]([CH2:18][NH2:19])[CH2:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>>[F:21][C:2]([F:20])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[O:16][CH:15]([CH2:18][NH:19][C:32](=[O:33])[O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH2:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCC1Cc2cccc(-c3ccc(C(F)(F)F)cc3)c2O1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cccc(-c3ccc(C(F)(F)F)cc3)c2O1)OCc1ccccc1
Yield: 90.7 %

Procedure:
Treatment of (±)-1-{7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine (1.8 g, 6.14 mmol) with diisopropylethylamine (1.06 g, 8.20) and benzyl chloroformate (1.12 g, 6.56 mmol) generally according to the procedure described for Intermediate 12 afforded 2.38 g (91%) of (±)-benzyl {7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methylcarbamate as a white solid. Rf=0.48 (silica, ethyl acetate:hexanes 1:4); mp 100-102° C.; Anal. calcd. for C24H20F3NO3: C, 67.44; H, 4.72; N, 3.28. Found: C, 67.37; H, 4.69; N, 3.15.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:33][CH:32]([N:34]2[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35]2)[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:30]4[CH2:33][CH:32]([N:34]5[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35]5)[CH2:31]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: O[C@H]1CCN(C2CNC2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CC[C@H](O)C4)C3)n(C)c2n1
Reaction time: 65 h
Yield: 52.8 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (100 mg, 0.26 mmol), (S)-1-azetidin-3-ylpyrrolidin-3-ol (41 mg, 0.28 mmol) and 4 Å powdered molecular sieves (200 mg) in DCE (6 mL) was stirred at room temperature for 2 h before the addition of sodium triacetoxyborohydride (108 mg, 0.51 mmol). The reaction mixture was stirred for 65 h then filtered through celite, washing with DCM. The organic phase was washed with brine (×1) and concentrated in vacuo. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-15%) affording 536 as a yellow foam (71 mg, 53%). LCMS (Method I): RT 2.31 min [M+H]+ 518.2. 1H NMR (CDCl3, 400 MHz): δ 8.02-7.97 (m, 1 H); 7.76-7.71 (m, 1 H); 7.29-7.22 (m, 2 H); 4.53 (bs, 1 H); 4.35 (m, 4 H); 3.96 (s, 2 H); 3.90-3.82 (m, 7 H); 3.67 (bs, 2 H); 3.55 (m, 3 H); 3.34 (q, J=7.5 Hz, 2 H); 3.17 (m, 1 H); 2.99 (m, 1 H); 2.30 (m, 2 H); 2.02 (m, 2 H) and 1.44 (t, J=7.5 Hz, 3 H)
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][CH:13]2[C:18]([OH:20])=[O:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:23])=[N-]>CCOCC>[C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][CH:13]2[C:18]([O:20][CH3:23])=[O:19])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(c1ccccc1)c1cccc2c1CCC2C(=O)O
Solvent: CCOCC
Product: COC(=O)C1CCc2c(C(=O)c3ccccc3)cccc21
Reaction time: 0.5 h

Procedure:
In 50 ml. of ether is dissolved 2.7 g. of 4-benzoylindan-1-carboxylic acid and, then, an ethereal solution of diazomethane is added until the yellow color of the solution has not disappeared. The solution is then allowed to stand for 30 minutes, after which the excess diazomethane and the ether are distilled off. The methyl 4-benzoylindan-1-carboxylate thus obtained as the distillation residue is dissolved in 50 ml. of dimethylsulfoxide and under stirring, the solution is added dropwise to 100 ml. of dimethylsulfoxide containing 1.5 g. of sodium hydride over a period of 15 minutes.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.C=CC=C>>[CH2:4]1[C:5]2[C:6](=[O:16])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13](=[O:15])[C:14]=2[CH2:1][CH2:2][CH2:3]1
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Agent: C=CC=C
Product: O=C1C2=C(CCCC2)C(=O)c2ccccc21

Procedure:
The liquid taken off at the sump of the quencher is divided into two partial streams. One partial stream, for example about 0.1 to 10%, preferably about 0.3 to 1.5%, of the total stream, is withdrawn from the system. This partial stream which is withdrawn contains the naphthoquinone and phthalic anhydride, isolated by the process according to the invention, in the form of a solution in naphthalene. This process product can be worked up to give pure naphthoquinone and pure phthalic anhydride but it is preferably further used directly, for example for the preparation of anthraquinone by reacting the process product with butadiene to give tetrahydroanthraquinone and subsequently converting this to anthraquinone. Preferably, the amount of process product which is withdrawn from the process corresponds to the amount of naphthoquinone and phthalic anhydride which is introduced into the quencher with the feed gas.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:6]2[CH:14]=[CH:15][C:16]([C:18]([OH:20])=O)=[CH:17][C:5]=2[N:4]=1.S(Cl)(Cl)=O.[NH2:25][C:26]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[CH:28][C:27]=1O.C(N(CC)CC)C.CS(O)(=O)=O.C(=O)([O-])O.[Na+]>O.O1CCCC1>[N+:32]([C:30]1[CH:29]=[CH:28][C:27]2[O:20][C:18]([C:16]3[CH:15]=[CH:14][C:6]4[N:7]([CH:8]5[CH2:9][CH2:10][O:11][CH2:12][CH2:13]5)[C:3]([CH3:2])=[N:4][C:5]=4[CH:17]=3)=[N:25][C:26]=2[CH:31]=1)([O-:34])=[O:33]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: Cc1nc2cc(C(=O)O)ccc2n1C1CCOCC1
Agent: CS(=O)(=O)O
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1nc2cc(-c3nc4cc([N+](=O)[O-])ccc4o3)ccc2n1C1CCOCC1
Yield: 19.6 %

Procedure:
To 2-methyl-1-(tetrahydropyran-4-yl)benzimidazole-5-carboxylic acid HCl salt (see Working Example 4-3) (264 mg, 0.888 mmol) was added thionyl chloride (2 mL), and this was stirred at reflux for 3 hours. After the reaction was complete, concentration at reduced pressure gave a residue that was added to 2-amino-4-nitrophenol (137 mg, 0.888 mmol), triethylamine (449 mg, 4.44 mmol) and tetrahydrofuran (10 mL), and this was stirred at room temperature for 14 hours. After the reaction was complete, this was concentrated, and to a dioxane (5 mL) solution of the residue obtained was added methanesulfonic acid (140 mg, 1.46 mmol), and this was heated to reflux for 18 hours. After the reaction solution was cooled, water and saturated aqueous sodium hydrogen carbonate solution were added, and this was extracted with chloroform. After the organic layer obtained was dried over anhydrous sodium sulfate, it was filtered and concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (66 mg, 20% yield) as white crystals.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([O:13]C)[C:5]([CH:10]([CH3:12])[CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=1.B(Br)(Br)Br.O>ClCCl>[I:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH:10]([CH3:12])[CH3:11])=[C:4]([OH:13])[CH:3]=1
Reactant: COc1cc(I)cc(OC)c1C(C)C
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: COc1cc(I)cc(O)c1C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.7 %

Procedure:
To a solution of 5-Iodo-2-isopropyl-1,3-dimethoxy-benzene (805 mg, 2.63 mmol) in anhydrous dichloromethane (26 mL) at 0° C. was added boron tribromide (2.63 mL, 2.63 mmol) 1M in dichloromethane), maintaining the temperature of the reaction at 0° C. during the addition. After stirring at room temperature for 18 hours, water (10 mL) was slowly added to the reaction. After stirring 30 minutes, the dichloromethane layer was collected, dried using anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification of the residue by silica gel column chromatography eluting with 90/10 hexane/ethyl acetate yielded 5-Iodo-2-isopropyl-3-methoxy-phenol (612 mg, 80%) as an oil, MS (M+H)=293.
Reaction SMILES: [C:1]1([C:7]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:9][C@H:8]2[CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)([O-:23])=[O:22].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([O:13][C:12](=[O:14])[CH2:11][CH2:10][C@@H:8]2[CH2:9][C:7]2([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:26][CH:25]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(O)CC[C@@H]1CC1(c1ccccc1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CC[C@@H]1CC1(c1ccccc1)c1ccccc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
As in Example 111, (R)-2,2-diphenylcyclopropanepropanoic acid (6.1 g) and 4-nitrophenol (3,8 g) in dichloromethane (100 mL) was treated with 1,3-dicyclohexylcarbodiimide (4.7 g) and the mixture was stirred at 30° C. for 1 hour. The product obtained from the usual work up was crystallized from 2-propanol to yield 6.4 g of (R)-2,2-diphenylcyclopropanepropanoic acid 4-nitrophenyl ester, mp 77.5°-76.5° C.; [α]D25 +93.7° (c, 1.0, MeOH)
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:4]=[C:5]2[C:10]=1[CH:9]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:7]=[C:6]2[CH2:15]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:44]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[N:3]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:4]=[C:5]2[C:10]=1[CH:9]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:7]=[C:6]2[CH2:15][Br:44]
Reactant: O=C1CCC(=O)N1Br
Reactant: C[Si](C)(C)CCOCn1nc2c(CO)cc(C(F)(F)F)cc2c1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1nc2c(CBr)cc(C(F)(F)F)cc2c1Br
Temperature: 0 °C
Reaction time: 16 h

Procedure:
(3-Bromo-5-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)methanol (198 mg, 0.48 mmol) and triphenylphosphine (253 mg, 0.96 mmol) were combined in tetrahydrofuran (3 mL) and cooled to 0° C. N-Bromosuccinimide (180 mg, 1.01 mmol) was introduced in portions and the reaction allowed to warm to room temperature. After 16 h, the reaction mixture was diluted with ethyl acetate, washed with sodium bicarbonate (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (5% ethyl acetate/hexanes) gave 140 mg (61%) as a light brown oil. 1H-NMR (CDCl3, 300 MHz) δ 7.90 (s, 1H), 7.64 (s, 1H), 5.94 (s, 2H), 4.95 (s, 2H), 3.51-3.57 (m, 2H), 0.82-0.87 (m, 2H), 0.08 (s, 9H).
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[NH:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([C:16]4[C:17]([CH3:31])=[CH:18][C:19]([O:22][CH2:23][C:24]([CH3:30])([CH3:29])[C:25]([O:27]C)=[O:26])=[N:20][CH:21]=4)=[CH:12][C:11]=3[F:32])=[N:7][CH:6]=2)[CH2:3][CH2:2]1.[OH-].[Na+].O.C(O)(=O)C>O1CCCC1.CO>[CH:1]1([CH2:4][C:5]2[NH:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([C:16]4[C:17]([CH3:31])=[CH:18][C:19]([O:22][CH2:23][C:24]([CH3:29])([CH3:30])[C:25]([OH:27])=[O:26])=[N:20][CH:21]=4)=[CH:12][C:11]=3[F:32])=[N:7][CH:6]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)C(C)(C)COc1cc(C)c(-c2ccc(-c3ncc(CC4CC4)[nH]3)c(F)c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cc(OCC(C)(C)C(=O)O)ncc1-c1ccc(-c2ncc(CC3CC3)[nH]2)c(F)c1
Temperature: 50 °C
Reaction time: 7 h
Yield: 141.8 %

Procedure:
In tetrahydrofuran (10 mL) and methanol (10 mL) was dissolved methyl 3-[(5-{4-[5-(cyclopropylmethyl)-1H-imidazol-2-yl]-3-fluorophenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoate (247 mg), and after adding 2N aqueous sodium hydroxide solution (2.8 mL) to the solution, the resulting mixture was stirred at 50° C. for 7 hours. Water and acetic acid were added to the residue obtained by concentrating the reaction mixture under reduced pressure. The precipitated solid was collected by filtration, washed with water and dried to obtain 3-[(5-{4-[5-(cyclopropylmethyl)-1H-imidazol-2-yl]-3-fluorophenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoic acid (339 mg).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([OH:19])=[C:10]([C:16]([OH:18])=O)[N:11]=[C:12]2[Cl:15])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl.C[O:22][C:23](=[O:27])[C@H:24]([CH3:26])[NH2:25]>>[CH:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([OH:19])=[C:10]([C:16]([NH:25][C@@H:24]([CH3:26])[C:23]([OH:27])=[O:22])=[O:18])[N:11]=[C:12]2[Cl:15])=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc2c(O)c(C(=O)O)nc(Cl)c2c1
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Product: CC(C)Oc1ccc2c(O)c(C(=O)N[C@@H](C)C(=O)O)nc(Cl)c2c1

Procedure:
Analogously to Example A-56, 0.040 g of 7-isopropoxy-1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid were allowed to react with 0.020 g of L-Alanine methyl ester hydrochloride to give, after hydrolysis of the intermediate ester, 0.047 g of a white solid: MS-(−)-ion, M−1=353.1 amu.
Reaction SMILES: Br[CH:2](Br)[C:3]1[CH:4]=[CH:5][C:6]([N+:15]([O-:17])=[O:16])=[C:7]2[C:12]=1[O:11][C:10]([CH3:13])=[CH:9][C:8]2=[O:14].C[N+]1([O-])CC[O:23]CC1>C(#N)C>[CH3:13][C:10]1[O:11][C:12]2[C:7]([C:8](=[O:14])[CH:9]=1)=[C:6]([N+:15]([O-:17])=[O:16])[CH:5]=[CH:4][C:3]=2[CH:2]=[O:23]
Reactant: C[N+]1([O-])CCOCC1
Reactant: Cc1cc(=O)c2c([N+](=O)[O-])ccc(C(Br)Br)c2o1
Solvent: CC#N
Product: Cc1cc(=O)c2c([N+](=O)[O-])ccc(C=O)c2o1

Procedure:
175 mg (0.47 mmol) of 8-(dibromomethyl)-2-methyl-5-nitro-4H-chromen-4-one are heated under reflux with 151 mg (1.29 mmol) of N-methylmorpholine N-oxide with the addition of molecular sieves in 15 ml of acetonitrile overnight. After filtration through kieselguhr, the solvent is removed in vacuo, and the residue is purified by preparative HPLC. 23 mg (24% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[N:11]=[C:10]([C:12](=[C:15]2[NH:19][C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:17][S:16]2)[C:13]#[N:14])[CH:9]=[CH:8][N:7]=1.[C:24]1(=O)[O:29][C:27](=[O:28])[CH2:26][CH2:25]1.CN1CCOCC1.C(O)(C(F)(F)F)=O>CC(N(C)C)=O.C(Cl)Cl.CCOCC.O>[C:20]([C:18]1[NH:19][C:15](=[C:12]([C:10]2[CH:9]=[CH:8][N:7]=[C:6]([NH:5][CH2:4][CH2:3][CH2:2][N:1]3[C:27](=[O:28])[CH2:26][CH2:25][C:24]3=[O:29])[N:11]=2)[C:13]#[N:14])[S:16][CH:17]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)(C)C1=CSC(=C(C#N)c2ccnc(NCCCN)n2)N1
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C1=CSC(=C(C#N)c2ccnc(NCCCN3C(=O)CCC3=O)n2)N1
Temperature: 250 °C
Reaction time: 2 h
Yield: 140.6 %

Procedure:
To a suspension of {2-[(3-aminopropyl)amino]pyrimidin-4-yl}(4-tert-butyl-1,3-thiazol-2(3H)-ylidene)acetonitrile (200 mg, 0.61 mmol) in DMA in a microwave tube (X2) were added succinic anhydride (122 mg, 1.21 mmol) and NMM (0.133 mL, 1.21 mmol) and after sonication the solution was heated up to 250° C. on normal absorption for 15 min. Both tubes were gathered and 10 mL of water were added then the suspension was left at 4° C. for ON. The solid obtained was filtered off through paper and washed with water (3×) then dried under vacuum at 40° C. for 5 days, affording the crude title compound as a brown powder. The solid was taken up in DCM then an excess TFA was added. To the black solution was added ether and the suspension was left at 4° C. for 2 h. The precipitate formed was filtered off then washed with ether (3×), affording 353.9 mg of the title compound as a TFA salt (HPLC (max plot) 92%).