Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][N:14]([CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[NH:23][C:22]1=[O:28])[C:15]2=[O:20].[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35](Cl)=[O:36]>C1COCC1>[O:28]=[C:22]1[CH:21]([N:14]2[CH2:13][C:12]3[C:16](=[CH:17][CH:18]=[CH:19][C:11]=3[CH2:10][NH:9][C:35]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=3)=[O:36])[C:15]2=[O:20])[CH2:26][CH2:25][C:24](=[O:27])[NH:23]1
Reactant: O=C(Cl)c1ccccn1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3c(CNC(=O)c4ccccn4)cccc3C2=O)C(=O)N1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 75.5 %

Procedure:
Triethylamine (0.7 g, 7.4 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and picolinoyl chloride hydrchloride (0.5 g, 2.5 mmol) in THF (30 mL) at 5-10° C. After stirring at 5° C. for 10 minutes, the mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was stirred with H2O (30 mL). The mixture was filtered, and the solid was slurried with hot methanol (15 mL) to give pyridine-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide (0.6 g, 78%): mp 254-256° C.; 1H NMR (DMSO-d6) δ 2.01-2.06 (m, 1H), 2.32-2.66 (m, 2H), 2.86-3.01 (m, 1H), 4.43-4.65 (m, 4H, 2CH2), 5.12-5.19 (dd, J=4.7 and 13.0 Hz, 1H, CH), 7.45-7.64 (m, 4H, Ar), 7.97-8.07 (m, 2H, Ar), 8.65 (d, J=4.2 Hz, 1H, Ar), 9.51 (t, J=5.8 Hz, 1H, NH), 11.03 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.59, 31.17, 46.30, 51.57, 121.63, 122.02, 126.60, 128.28, 130.77, 131.58, 134.73, 137.79, 140.08, 148.44, 149.80, 164.16, 168.06, 170.99, 172.82; Anal. calcd. for C20H18N4O4: C, 63.49; H, 4.79; N, 14.81. Found: C, 63.32; H, 4.66; N, 14.80.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[OH:25][CH2:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>>[CH3:24][N:21]1[CH2:22][CH2:23][N:18]([C:15]2[CH:14]=[CH:13][C:12]([NH:11][C:8]3[N:7]=[CH:6][C:5]4=[CH:4][CH:3]=[C:2]([C:29]5[CH:28]=[C:27]([CH2:26][OH:25])[CH:32]=[CH:31][CH:30]=5)[N:10]4[N:9]=3)=[CH:17][CH:16]=2)[CH2:19][CH2:20]1
Reactant: OCc1cccc(B(O)O)c1
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5cccc(CO)c5)n4n3)cc2)CC1
Yield: 81.4 %

Procedure:
Analogous to Example 1497, (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (0.125 g, 0.323 mmol) and (3-Hydroxymethylphenyl)-boronic acid (98.1 mg, 0.646 mmol) were reacted to afford (3-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-phenyl)-methanol (109 mg; Yield=81.5%). LCMS (HPLC): 0.74 min, m/z=415 (M+H); 1H-NMR (DMSO-d6): 9.22 (s, 1H), 8.93 (s, 1H), 8.19 (s, 1H), 7.99 (d, 1H, J=7.8 Hz), 7.64 (d, 2H, J=9.0 Hz), 7.49 (m, 1H), 7.37 (d, 1H, J=7.6 Hz), 7.13 (d, 1H, J=4.7 Hz), 6.92 (m, 3H), 5.25 (t, 1H, J=5.8 Hz), 4.60 (d, 2H, J=5.8 Hz), 3.08 (m, 4H), 2.46 (m, 4H), 2.23 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:12]=1[CH2:13]Br.[H-].[Na+]>CN(C)C=O>[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:12]=1[CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: Clc1cccc(Cl)c1CBr
Reactant: O=Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2c(Cl)cccc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 107.6 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (3.59 g, 24.39 mmol) and 2,6-dichlorobenzyl bromide (7.05 g, 29.39 mmol) in dimethylformamide (20 mL) at 0° C. was added 60% sodium hydride (1.176 g, 29.39 mmol). After stirring at ambient temperature for 16 h, the reaction was partitioned between ethyl acetate and water. The organic layer was washed with aqueous sodium chloride and dried (MgSO4). Purification by flash column chromatography (silica gel, hexane/ethyl acetate) yielded the title compound as an off-white solid (7.38 g, 89%).
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][NH:2]1.[H-].[Na+].[CH3:14][O:15][C:16](=[O:25])[CH:17](Br)[CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.O>O1CCCC1>[CH3:14][O:15][C:16](=[O:25])[CH:17]([N:2]1[N:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]1=[O:11])[CH2:18][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=c1[nH]ncc2ccccc12
Reactant: COC(=O)C(Br)CC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(CC1CCCC1)n1ncc2ccccc2c1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 65.1 %

Procedure:
A solution of 2H-phthalazin-1-one (1.33 g, 9.1 mmol) in tetrahydrofuran (45.5 mL, 0.2M) cooled to 0° C. was treated with a 60% dispersion of sodium hydride in mineral oil (437 mg, 10.9 mmol). The reaction was stirred at 0° C. for 5 min and then at 25° C. for 30 min. After this time, the reaction was treated with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10, 2.35 g, 10 mmol). The reaction was then warmed to 50° C. where it stirred overnight. At this time, the reaction was cooled to 25° C., poured into water (100 mL), and extracted with methylene chloride (3×100 mL). The organics were dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (ISCO, 80 g, 20-50% ethyl acetate/hexanes) afforded 3-cyclopentyl-2-(1-oxo-1H-phthalazin-2-yl)-propionic acid methyl ester (1.78 g, 61%) as a clear oil; ES+-HRMS m/e calcd for C17H20N2O3 [M+H+] 301.1547 found 301.1546.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([O:19]CC)=[O:18])=[CH:5]2)[CH2:3][CH2:2]1>S(=O)(=O)(O)O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([F:14])[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Temperature: 100 °C
Yield: 95.9 %

Procedure:
A suspension of 7.85 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, ethyl ester in 220 ml of 2N sulfuric acid was heated at 100° C. overnight, then cooled in an ice bath. The solid was collected, washed with water and dried, giving 6.81 g of the desired compound, mp 292°-293° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH3:11])[CH2:6]O.P(Br)(Br)[Br:13]>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH3:11])[CH2:6][Br:13]
Reactant: BrP(Br)Br
Reactant: COc1cc(CO)ccc1C
Solvent: CCOCC
Product: COc1cc(CBr)ccc1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 187.3 %

Procedure:
A solution of 18.3 g (0.12 mol) of 3-methoxy-4-methylbenzyl alcohol in 150 mL of Et2O was treated with 23.8 g (0.12 mol) of BaCO3 and the mixture cooled in ice. This was treated dropwise with 5.8 mL (0.06 mol) of PBr3. After stirring at 0° C. for 15 minutes, the mixture was allowed to stir at room temperature overnight. The mixture was filtered and the solid washed with Et2O. The Et2O was washed with saturated NaHCO3, then with saturated NaCl. Drying over MgSO4 and removal of the solvent under reduced pressure left 24.17 g (93.5% yield) of the product as an oil. The structure was confirmed by NMR spectroscopy.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](=[O:30])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)=[CH:14][CH:13]=2)[CH:6]=1.[Li+].[OH-]>>[CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][C:20]=1[CH2:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]([C:7]2[CH:6]=[C:5]([CH2:4][C:3]([OH:31])=[O:2])[CH:10]=[CH:9][CH:8]=2)=[O:30])=[CH:17][CH:16]=1
Reactant: COC(=O)Cc1cccc(C(=O)c2ccc(OCc3ccc4ccccc4c3)cc2)c1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cc1cccc(C(=O)c2ccc(OCc3ccc4ccccc4c3)cc2)c1
Reaction time: 8 h
Yield: 99.3 %

Procedure:
A solution of the ester (1.29 g, 3.15 mmole) of Step A, is treated dropwise with 1N-LiOH and the mixture is stirred under nitrogen overnight. The solvent is evaporated and the residue is dissolved in water, acidified in the cold with 10% acetic acid (to pH 3) and extracted with ethyl acetate (3×). The extracts are dried (MgSO4) and evaporated to dryness. The residue (1.24 g, quantitative yield) is recrystallized by dissolving it in a relatively large volume of warm ethyl acetate-dichloromethane followed by concentrating to half volume. The precipitate is collected and dried at 45° C. in vacuo (0.610 g, 48.8%), m.p. 150°-152° C.
Reaction SMILES: C([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([CH3:17])[CH:5]=1)(=O)C.C1C=C(Cl)C=[C:20]([C:25]([O:27]O)=[O:26])C=1>ClCCl>[C:25]([O:27][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([CH3:17])[CH:5]=1)(=[O:26])[CH3:20]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)COc1ccc(C(C)=O)cc1C
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(OC(C)=O)cc1C
Temperature: 25 °C
Yield: 72 %

Procedure:
A solution of ethyl 2-(4-acetyl-2-methylphenoxy)acetate (683) (8.78 g, 37 mmol), mCPBA (2.eq.), and p-TsOH monohydrate (0.15 eq.) in dichloromethane (160 mL) was heated at 40° C. overnight. The reaction was cooled to room temperature and washed with 1M KI (2×200 mL), 5% NaHSO3 (2×150 mL), and water (200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-100% EtOAc in hexanes) to provide ethyl 2-(4-acetoxy-2-methylphenoxy)acetate (684) (72%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[O:15][N:14]=[C:13]([CH2:16][CH2:17][CH3:18])[N:12]=2)=[CH:5][C:4]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21].B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[O:15][N:14]=[C:13]([CH2:16][CH2:17][CH3:18])[N:12]=2)=[CH:5][C:4]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: CCCc1noc(C=Cc2ccc(OC)c(NS(C)(=O)=O)c2)n1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCc1noc(C=Cc2ccc(O)c(NS(C)(=O)=O)c2)n1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
N-{2-Methoxy-5-[2-(3-propyl-[1,2,4]oxadiazol-5-yl)-vinyl]-phenyl}-methane sulfonamide (compound of Example 9; 0.08 g, 0.23 mmol) was dissolved in dichloromethane (7 mL) and cooled to −78° C. A solution of boron tribromide in dichloromethane (0.15 mL, 1.61 mmol) was cooled to −78° C. and slowly added to the reaction mixture. After 1.5 h, the reaction mixture was warmed to room temperature and stirred for 3 h. At the end of 3 h, the mixture was quenched by dropwise addition of methanol (5 mL) at 0° C. and stirred for 20 min at room temperature. The solvent was evaporated, and the residue was redissolved in a mixture of 10% methanol in chloroform at 0° C. Solid sodium carbonate was added to this solution to adjust pH to 8. The solvent was evaporated and the crude product obtained was purified by column chromatography (silica gel, 0.5% methanol in chloroform) to afford the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[NH:11][C:12]([CH:15]=O)=[C:13]([CH3:14])[C:7]=2[C:6]1=[O:17].[Cl:19][C:20]1[CH:21]=[C:22]([NH:27][C:28]2[C:29]3[CH2:36][C:35](=[O:37])[NH:34][C:30]=3[N:31]=[CH:32][N:33]=2)[CH:23]=[CH:24][C:25]=1[F:26]>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:27][C:28]2[C:29]3[C:36](=[CH:15][C:12]4[NH:11][C:8]5[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][N:2]([CH3:18])[CH3:1])[C:6](=[O:17])[C:7]=5[C:13]=4[CH3:14])[C:35](=[O:37])[NH:34][C:30]=3[N:31]=[CH:32][N:33]=2)[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CC2
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Product: Cc1c(C=C2C(=O)Nc3ncnc(Nc4ccc(F)c(Cl)c4)c32)[nH]c2c1C(=O)N(CCN(C)C)CC2
Yield: 61.5 %

Procedure:
The title compound was prepared under the same conditions as described in Example 102 with 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (prepared according to Bioorganic&Medicinal Chemistry Letters, 12 (16), 2153-2157, 2002) as starting materials to give 4-(3-chloro-4-fluoro-phenylamino)-5-[5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (240 mg, 61.5%) as a yellow solid.
Reaction SMILES: [OH:1]C1C=CC=C2C=1C=CC(=O)N2.OC1C=CC=C2C=1C=CC=N2.[OH-].[Na+].[OH-].[K+].[OH:28][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:38]=1[NH:37][C:36](=O)[CH:35]=[CH:34]2.OC1C=CC=C2C=1N=CC=C2.OO>C(O)(=O)C>[OH:28][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:38]=1[N+:37]([O-:1])=[CH:36][CH:35]=[CH:34]2
Reactant: O=c1ccc2c(O)cccc2[nH]1
Reactant: O=c1ccc2cccc(O)c2[nH]1
Agent: OO
Agent: Oc1cccc2cccnc12
Agent: Oc1cccc2ncccc12
Solvent: CC(=O)O
Product: [O-][n+]1cccc2cccc(O)c21

Procedure:
The 5-, 6-, 7- and 8-hydroxycarbostyrils used for the preparation of the starting material used in the present invention are described in Berichte, Vol. 20, page 2172, 1887; Journal of Organic Chemistry, Vol. 36, pp 3490-3493, 1971 and ibid, Vol. 33, pp 1089-1092, 1968. Briefly, 5-hydroxycarbostyril can be prepared by fusing 5-hydroxyquinoline with a caustic alkali such as sodium hydroxide or potassium hydroxide, and 8-hydroxycarbostyril can be prepared by reacting 8-hydroxyquinoline with hydrogen peroxide in glacial acetic acid to produce 8-hydroxyquinoline 1-oxide which is then refluxed in acetic anhydride to obtain acetoxycarbostyril and hydrolyzing the resulting acetoxycarbostyril with concentrated hydrochloric acid to give the desired 8-hydroxycarbostyril. The 6- and 7-hydroxycarbostyrils can be prepared in a similar manner to those described above.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17]CC[C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][N:22]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[N:23]1.N1C=C(B(O)O)C=NC=1>>[N:13]1([C@H:11]2[CH2:10][C@H:9]([C:7]3[S:8][C:4]4[CH:3]=[C:2]([C:25]5[CH:24]=[N:23][N:22]([CH3:21])[CH:26]=5)[CH:20]=[CH:19][C:5]=4[N:6]=3)[CH2:12]2)[CH2:14][CH2:18][CH2:17]1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Agent: OB(O)c1cncnc1
Product: Cn1cc(-c2ccc3nc([C@H]4C[C@H](N5CCC5)C4)sc3c2)cn1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, except for substituting the product of Example 61A for the product of Example 1E, and substituting 1-methyl-1H-pyrazoleboronic acid pinacol ester for pyrimidine-5-boronic acid. 1H NMR (300 MHz, CDCl3) δ ppm 7.89-7.97 (m, 2H) 7.80 (s, 1H) 7.65 (s, 1H) 7.55 (dd, J=8.31, 1.86 Hz, 1H) 3.97 (s, 3H) 3.92-4.07 (m, 1H) 3.21-3.45 (m, 5H) 2.36-2.62 (m, 4H) 2.06-2.24 (m, 2H). MS: (M+H)+=325.
Reaction SMILES: [C:1]([C:3]1[N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=2)#[N:2].[Br:22]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:22][CH2:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[O:13][CH3:14])[N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3]([C:1]#[N:2])=[CH:11]2
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc2c(cc1C)cc(C#N)n2C(=O)OC(C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc2c(cc1CBr)cc(C#N)n2C(=O)OC(C)(C)C
Yield: 100.1 %

Procedure:
To a stirred solution of 174 mg of tert-butyl 2-cyano-6-methoxy-5-methyl-1H-indole-1-carboxylate (0.61 mmol) in carbon tetrachloride (2.5 mL) was added 108 mg of N-bromosuccinimide (0.61 mmol) and 11 mg of AIBN (0.065 mmol). The mixture was refluxed for 1 h, then cooled and concentrated and filtered through short silica gel plug using hexane-ethyl acetate 10:1 to give 223 mg of crude tert-butyl 5-(bromomethyl)-2-cyano-6-methoxy-1H-indole-1-carboxylate that was used in the next step without further purification.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][C:4]1[CH:5]=[C:6]([CH3:29])[C:7]2[N:8]=[C:9](OS(C(F)(F)F)(=O)=O)[C:10]3[CH:20]=[CH:19][CH:18]=[N:17][C:11]=3[N:12]([CH2:15][CH3:16])[C:13]=2[N:14]=1>C(Cl)Cl.C(OCC)(=O)C>[CH3:3][C:4]1[CH:5]=[C:6]([CH3:29])[C:7]2[N:8]=[C:9]([NH:2][CH3:1])[C:10]3[CH:20]=[CH:19][CH:18]=[N:17][C:11]=3[N:12]([CH2:15][CH3:16])[C:13]=2[N:14]=1
Reactant: CCN1c2ncccc2C(OS(=O)(=O)C(F)(F)F)=Nc2c(C)cc(C)nc21
Reactant: CN
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCN1c2ncccc2C(NC)=Nc2c(C)cc(C)nc21
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Methylamine (3 mL) was added to a solution of 2,4-dimethyl-11-ethyl-6-trifluoromethane-sulfonyloxy-11H-dipyrido[3,2-b:2',3'-e][1,4]diazepine (0.16 g, 0.4 mmole) in methylene chloride (0.5 mL). The mixture was sealed in a pressure bottle and stirred at room temperature for 4 days. The mixture was diluted with ethyl acetate, washed with water, dried, filtered and concentrated in vacuo to give crude product. This was purified by chromatography over silica gel (eluted 10% ethyl acetate/methylene chloride) and recrystallized from ethyl acetate/hexane to give 0.016 g of the title compound, m.p. 128°-130° C.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[C:6]1(=[O:12])[O:11][C:9](=[O:10])[CH:8]=[CH:7]1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:14].[Na+].[Na+].OO.[OH-].[Na+]>O>[C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[C:6]([OH:11])(=[O:12])/[CH:7]=[CH:8]\[C:9]([OH:14])=[O:10]
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: O=C1C=CC(=O)O1
Agent: C=CC(=O)O
Agent: OO
Agent: [Na+]
Solvent: O
Product: O=C(O)/C=C\C(=O)O
Reaction time: 0.33 h

Procedure:
In a 2.5-liters volume SUS-made separable flask equipped with a thermometer, a stirrer and a reflux condenser, was charged 282.8 g of ion-exchanged water (hereinafter referred to as “pure water”), and the aqueous solution was elevated to the boiling point in the reflux state while stirring. Next, 360.0 g of an 80% by weight acrylic acid aqueous solution (hereinafter referred to as “80% AA”), 98.0 g of maleic anhydride (hereinafter referred to as “MA”), 133.3 g of a 15% by weight sodium persulfate aqueous solution (hereinafter referred to as “15% NaPS”), 85.7 g of a 35% by weight hydrogen peroxide aqueous solution (hereinafter referred to as “35% H2O2), and 350.0 g of a 48% by weight sodium hydroxide aqueous solution (hereinafter referred to as “48% NaOH”) were continuously added dropwise at uniform rates from separate dropping nozzles over 180 minutes from the initiation of the polymerization, 150 minutes from the initiation of the polymerization, 190 minutes from the initiation of the polymerization, 120 minutes from the initiation of the polymerization, and 180 minutes from the initiation of the polymerization, respectively, while keeping the reflux state with stirring. After the completion of the dropwise addition of all of the aqueous solutions, the boiling point reflux state was kept over 20 minutes. Finally, 100.0 g of 48% NaOH was added to the reaction mixture to complete the polymerization.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([OH:14])=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Li+].[CH3:17][Li].Cl>COCCOC.CCOCC.O>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([CH2:11][C:12](=[O:14])[CH3:17])[CH2:9][CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: [Li]C
Reactant: CC(C)(C)[C@H]1CC[C@H](CC(=O)O)CC1
Agent: Cl
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: COCCOC
Product: CC(=O)C[C@H]1CC[C@H](C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of trans-(4-t-butylcyclohexyl)acetic acid (9.96 g) in dry DME (30 ml) was added over 10 min to a vigorously stirred suspension of powdered lithium hydride (0.5 g) in dry DME (30 ml). The mixture was refluxed for 2.5 hr, cooled on ice and a solution of methyl lithium in ether (63 ml; 1.6M solution) added over 30 min. The mixture was then stirred at room temperature for 2 hr, and poured into a mixture of conc. hydrochloric acid (13.5 ml) and water (200 ml). The organic phase was separated and the residue extracted with ether. The extracts were combined, washed with aq. sodium carbonate and satd. brine, dried over magnesium sulphate and concentrated in vacuo. Distillation afforded the title compound (7.7 g), b.p. 90°-100°/0.3 mm, NMR δH (CDCl3) 2.28 (2H, d, J 7Hz), 2.12 (3H, s), 1.85-1.65 (6H, m), 1.05-0.85 (4H, m), 0.85 (9H, s).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:17][O:18][CH3:19])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:20])[C:3]=1[C:21]1[NH:26][C:25]2[CH:27]=[CH:28][C:29]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][C:24]=2[S:23](=[O:40])(=[O:39])[N:22]=1.[C:41](OC(=O)C)(=[O:43])[CH3:42]>N1C=CC=CC=1>[C:41]([N:17]([O:18][CH3:19])[C:5]1([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([OH:1])=[C:3]([C:21]2[NH:26][C:25]3[CH:27]=[CH:28][C:29]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[CH:30][C:24]=3[S:23](=[O:39])(=[O:40])[N:22]=2)[C:4]1=[O:20])(=[O:43])[CH3:42]
Reactant: CC(=O)OC(C)=O
Reactant: CONC1(CCC(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Solvent: c1ccncc1
Product: CON(C(C)=O)C1(CCC(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.4 %

Procedure:
To a solution of the product from Example 18B (23 mg, 0.04 mmol) in pyridine (0.5 mL) was added acetic anhydride (38 μL, 0.4 mmol). The reaction solution was stirred at room temperature for 18 h. After which, the solution was concentrated in vacuo. The resulting residue was taken up ethyl acetate (2 mL) and washed with aqueous 1 N HCl (2×1 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. Column chromatography on silica (1%→3%→5% methanol/dichloromethane) afforded the title compound as a yellow solid (17 mg, 68%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.34-0.52 (m, 1H), 0.58-0.76 (m, 6H), 0.88-1.04 (m, 1H), 1.20-1.37 (m, 2H), 1.50 (s, 9H), 2.04 (s, 3H), 7.53 (t, J=7.54 Hz, 2H), 7.62-7.77 (m, 3H), 8.07-8.17 (m, 2H), 9.89 (s, 1H), 13.49 (s, 1H); MS m/z 613.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][CH3:10].[Cl:11][C:12]1[CH:18]=[C:17]([Cl:19])[C:16]([Cl:20])=[CH:15][C:13]=1N>>[CH3:10][O:9][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([C:13]2[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:12]=2[Cl:11])=[C:5]([Cl:8])[CH:4]=1
Reactant: Nc1cc(Cl)c(Cl)cc1Cl
Reactant: COc1cc(Cl)ccc1Cl
Product: COc1cc(Cl)c(-c2cc(Cl)c(Cl)cc2Cl)cc1Cl

Procedure:
4-Methoxy-2,2',4',5,5'-pentachlorobiphenyl was prepared from 2,5-Dichloroanisole (35 g, 200 mmol) and 2,4,5-trichloroaniline (2.95 g, 15 mmol) according to the procedure in Example 2A. The excess dichloroanisole was removed by distillation and the residue was then filtered through silica gel (heptane eluent) and further purified [Chromatotron®, 4 mm silica gel, hexane, 20 mL/min] to give the product (980 mg). Mass spectrum: m/z at 354 for C13H7Cl5O.