Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[F:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[CH:12][C:13](=[O:32])[N:14]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19](B4OC(C)(C)C(C)(C)O4)[CH:18]=3)[N:15]=2)[CH:6]=[C:7]([F:9])[CH:8]=1.Br[C:34]1[N:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=1.C(=O)([O-])O.[Na+]>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.C(#N)C>[NH2:40][C:37]1[N:38]=[CH:39][C:34]([C:19]2[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=2)[CH2:16][N:14]2[C:13](=[O:32])[CH:12]=[CH:11][C:10]([C:5]3[CH:4]=[C:3]([F:2])[CH:8]=[C:7]([F:9])[CH:6]=3)=[N:15]2)=[N:35][CH:36]=1
Reactant: CC1(C)OB(c2cccc(Cn3nc(-c4cc(F)cc(F)c4)ccc3=O)c2)OC1(C)C
Reactant: Nc1cnc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Nc1cnc(-c2cccc(Cn3nc(-c4cc(F)cc(F)c4)ccc3=O)c2)cn1
Temperature: 80 °C

Procedure:
5 ml of water and 5 ml of acetonitrile are added to 150 mg (0.35 mmol) of 6-(3,5-difluorophenyl)-2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzyl]-2H-pyridazin-3-one, 63 mg (0.35 mmol) of 5-bromopyrazin-2-ylamine and 167 mg (1.99 mmol) of sodium hydrogencarbonate, and the mixture is degassed a number of times. Under an argon atmosphere, mg (0.017 mmol) of tetrakis(triphenylphosphine)palladium(0) are added, and the mixture is subsequently heated at 80° C. for 15 h with stirring. A further 20 mg (0.017 mmol) of tetrakis(triphenylphosphine)palladium(0) are subsequently added, and the mixture is stirred at 80° C. for a further 24 h. The hot suspension is filtered. The filtrate is concentrated to half. After cooling to room temperature, the resultant precipitate is filtered off with suction and washed with a little water. The residue is purified by means of preparative HPLC; yield: 21 mg of “A280”; HPLC: Rt=2.68 min (method C); LC-MS: 392 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=[N:6][C:7]=1Cl.[I:13][Si](C)(C)C.[I-].[Na+]>C(#N)CC>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=[N:6][C:7]=1[I:13]
Reactant: C[Si](C)(C)I
Reactant: COC(=O)c1cnc(Cl)c(Br)c1
Agent: [I-]
Agent: [Na+]
Solvent: CCC#N
Product: COC(=O)c1cnc(I)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a mixture of methyl 5-bromo-6-chloro-3-pyridinecarboxylate (1 g, 3.99 mmol) in propionitrile (30 ml) was added iodotrimethylsilane (0.689 ml, 3.99 mmol) and then sodium iodide (1.795 g, 11.98 mmol). The mixture was stirred at room temperature for 30 min. Solvent was evaporated and the obtained solid was dissolved in H2O. pH was adjusted to basic with 2M NaOH and DCM was added. The organic phase was extracted, dried over Na2SO4, filtered and concentrated to give 1.2 g (79%) of desired compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH:9]([CH3:17])[CH2:10][CH:11](O)[CH2:12][C:13](=[O:15])[CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH:9]([CH3:17])[CH2:10][CH:11]=[CH:12][C:13](=[O:15])[CH3:14]
Reactant: CC(=O)CC(O)CC(C)Sc1ccccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)C=CCC(C)Sc1ccccc1F
Yield: 73.1 %

Procedure:
1.00 Gram of 6-(2-fluorophenylthio)-4-hydroxy-2-heptanone was dissolved in 100 ml of toluene, and 0.02 g of p-toluene sulfonic acid was added thereto. The resulting mixture was refluxed for 2 hours with stirring. After having been cooled, the mixture was washed with a saturated aqueous sodium hydrogencarbonate solution and then saturated aqueous sodium chloride solution. Then the mixture was dried over anhydrous magnesium sulfate. Removing the solvent from the mixture under reduced pressure gave 0.84 g of 6-(2-fluorophenylthio)-3-hepten-2-one. (trans : cis =5.1 : 1) (purity: 80.6%). The yield was 73.1%.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12](=[O:17])[CH2:13]S(C)=O.[CH:18]([CH:20]1[CH2:22][CH:21]1[C:23]([O:25][CH2:26][CH3:27])=[O:24])=O.N1CCCCC1>C1(C)C=CC=CC=1>[O:17]=[C:12]1[CH:13]=[C:18]([CH:20]2[CH2:22][CH:21]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:1][C:2]2[C:11]3[C:6]([CH:5]=[CH:4][C:3]1=2)=[CH:7][CH:8]=[CH:9][CH:10]=3
Reactant: CCOC(=O)C1CC1C=O
Reactant: CS(=O)CC(=O)c1ccc2ccccc2c1O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC1c1cc(=O)c2ccc3ccccc3c2o1

Procedure:
A mixture of 12.4g of 1'-hydroxy-2-(methylsulfinyl)-2'-acetonaphthone, 7.1g of ethyl 2-formyl-1-cyclopropane carboxylate, 250ml of toluene and 0.5ml of piperidine was refluxed for 8 hrs. The toluene was then removed under reduced pressure, and the oily residue was recrystallized from Skelly B with the aid of charcoal, mp. 106°-07.5°; yield 6.5g (42%); λ max mμ (ε) 219 (50,000), 259 (36,800), 327 (3,990), 341 (4,100); ν max 760 (m), 825 (ms), 1195 (s), 1640 (s), 1650 (s), 1730 (s) cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH3:10])=[C:6]([CH:8]=1)[NH2:7].[O:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH:13]=[C:12]1[S:20](Cl)(=[O:22])=[O:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH3:10])=[C:6]([NH:7][S:20]([C:12]2[O:11][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH:13]=2)(=[O:21])=[O:22])[CH:8]=1
Reactant: CSc1ccc(Cl)cc1N
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Product: CSc1ccc(Cl)cc1NS(=O)(=O)c1cc2ccccc2o1
Yield: 59.7 %

Procedure:
Following General Procedure B, the title compound (243 mg, 60%) was prepared from 5-chloro-2-(methylthio)aniline (CAS 16423-54-4) (200 mg, 1.15 mmol) and 1-benzofuran-2-sulfonyl chloride (249 mg, 1.152 mmol).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[C:12](B(O)O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:18][C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C:12]2[C:11]3[C:6]([C:5]4[CH:4]=[CH:3][CH:2]=[CH:1][C:14]=4[CH:13]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:21][CH:20]=1
Reactant: OB(O)c1cc2ccccc2c2ccccc12
Reactant: Brc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2cc3ccccc3c3ccccc23)cc1
Reaction time: 24 h
Yield: 72.2 %

Procedure:
In argon atmosphere, a mixture of 39.25 g (177 mmol) of 9-phenanthreneboronic acid, 50.0 g (177 mmol) of 4-bromoiodobenzene, 4.10 g (3.54 mmol) of tetrakis(triphenylphosphine)palladium (0), 400 ml of toluene, and 265 ml of a 2 M sodium carbonate aqueous solution was refluxed under stirring for 24 h. After the reaction, the reaction mixture was filtered and the aqueous phase was removed. The organic phase was washed with water and dried over magnesium sulfate, and then the toluene was removed by distillation under reduced pressure. The residue was purified by silica gel chromatography to obtain 42.6 g (yield: 72%) of 9-(4-bromophenyl)phenanthrene.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]4[S:17][CH:18]=[CH:19][N:20]=4)[CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#N.C(O)=[O:24]>O.[Ni]>[CH:1]([C:3]1[CH:22]=[CH:21][C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]4[S:17][CH:18]=[CH:19][N:20]=4)[CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)=[O:24]
Reactant: O=CO
Reactant: N#Cc1ccc2c(c1)ncn2-c1cccc(-c2nccs2)c1
Agent: [Ni]
Solvent: O
Product: O=Cc1ccc2c(c1)ncn2-c1cccc(-c2nccs2)c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
Raney Ni (2.0 g) was added to a solution of (54) (1.5 g, 4.9 mmol) in HCO2H (18 ml) and water (6 ml). The mixture was stirred under argon at 110° C. for 1 hr. After cooling the mixture was filtered. The filtrate was concentrated, partitioned between a 5% aqueous NaHCO3 solution and ethyl acetate. The organic phase was washed with brine, dried and concentrated under reduced pressure to give (55) (1.3 g, 87%).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:5][C:6](=[O:8])[N:7]=1.[N:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]([CH:40]([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][N:59]=[C:60]=[O:61])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[C:19]=[O:20]>N1C=CC=CC=1>[CH2:30]([CH:29]([CH:40]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][NH:59][C:60]([NH:1][C:2]1[NH:3][C:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:5][C:6](=[O:8])[N:7]=1)=[O:61])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][NH:18][C:19]([NH:1][C:2]1[NH:3][C:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:5][C:6](=[O:8])[N:7]=1)=[O:20])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCCC(CCCCCCCCN=C=O)C(CCCCCCCCCC)CCCCCCCCN=C=O
Reactant: CCCCCCCCCc1cc(=O)nc(N)[nH]1
Solvent: c1ccncc1
Product: CCCCCCCCCCC(CCCCCCCCNC(=O)Nc1nc(=O)cc(CCCCCCCCC)[nH]1)C(CCCCCCCCCC)CCCCCCCCNC(=O)Nc1nc(=O)cc(CCCCCCCCC)[nH]1
Reaction time: 24 h
Yield: 97.2 %

Procedure:
In a 250 mL round-bottomed flask was added 2-amino-6-nonylpyrimidin-4(1H)-one (1.88 g, 7.92 mmol) in Pyridine 50 mL to give a white suspension. The mixture was heated to 50 deg/C. 11,12-bis(8-isocyanatooctyl)docosane (2.327 g, 3.77 mmol) was dissolved in 5-10 mL of pyridine and added all at once to the mixture. The reaction was heated to 75 deg/C. and stirred for 24 h. The pyridine was removed and the residue was taken up in chloroform and the viscous solution was dripped into a rapidly stirring solution (500 mL) of MeOH upon which a white solid formed. The solution was decanted off and the residue was taken up in MeOH (10 ml) and rapidly stirred for 1 h. The product was collected by vacuum filtration dried under vacuum to give 4 g of 1,1′-(9,10-didecyloctadecane-1,18-diyl)bis(3-(6-nonyl-4-oxo-1,4-dihydropyrimidin-2-yl)urea).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1.[C:8](OC(=O)C)(=[O:10])[CH3:9]>C(Cl)Cl.N1C=CC=CC=1>[C:8]([NH:1][C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1)(=[O:10])[CH3:9]
Reactant: Nc1ncc(Br)s1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ncc(Br)s1
Temperature: 25 °C

Procedure:
To a solution of 2-amino-5-bromothiazole (22.3 g, 85.9 mmol) in methylene chloride (100 mL) and pyridine (60 mL) was added acetic anhydride (11 mL) slowly with stirring. The mixture was allowed to stir for 2.5 hours, warmed to room temperature, and stirred for an additional 4 hours. Most of the solvent was removed in vacuo and the residue was washed with ethyl acetate and aqueous HCl. The organic solution was then washed with water, dried over MgSO4 and concentrated to give a crude solid. This solid was triturated with Et2O, filtered, washed with Et2O, and dried to give 2-acetamido-5-bromothiazole as a solid (15.1 g, 80%, C5H5BrN2OS, MS m/e 222 (M+H)+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH2:6][C:5]12[N:20]=[C:19]([NH2:21])[C:18]([CH3:22])=[N:17]1.[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[F:30]>>[Cl:23][C:24]1[CH:25]=[C:26]([C:2]2[CH:3]=[C:4]3[C:14](=[CH:15][CH:16]=2)[O:13][C:7]2([CH2:12][CH2:11][CH2:10][O:9][CH2:8]2)[CH2:6][C:5]23[N:20]=[C:19]([NH2:21])[C:18]([CH3:22])=[N:17]2)[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: CC1=NC2(CC3(CCCOC3)Oc3ccc(Br)cc32)N=C1N
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: CC1=NC2(CC3(CCCOC3)Oc3ccc(-c4ccc(F)c(Cl)c4)cc32)N=C1N
Yield: 38 %

Procedure:
6′-Bromo-5-methyl-5″,6″-dihydro-4″H-dispiro[imidazole-2,4′-chromene-2′,3″-pyran]-4-amine (Example 45 Isomer 1, 77 mg, 0.21 mmol) and 3-chloro-4-fluorophenylboronic acid (47.9 mg, 0.27 mmol) were reacted using the conditions described for Example 46a Isomer 1, to give Isomer 1 of the title compound (33 mg, 38% yield) with undetermined configuration: 1H NMR (500 MHz, DMSO-d6) δ ppm 1.44-1.52 (m, 1 H), 1.81-1.92 (m, 3 H), 1.97-2.05 (m, 2 H), 2.22 (s, 3 H), 3.41-3.48 (m, 1 H), 3.56 (d, 1 H), 3.67-3.74 (m, 1 H), 3.98 (d, 1 H), 6.57 (s, 2H), 6.60 (d, 1 H), 6.94 (d, 1 H), 7.38-7.46 (m, 3 H), 7.60 (dd, 1 H); MS (ES+) m/z 414 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:6]([N:8]([CH2:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[O:21][CH2:22][CH2:23][OH:24])[C:9](=[O:11])[CH3:10])[CH:7]=1.C(N(C(C)C)CC)(C)C.[S:41](Cl)([CH3:44])(=[O:43])=[O:42]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[C:6]([N:8]([CH2:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[O:21][CH2:22][CH2:23][O:24][S:41]([CH3:44])(=[O:43])=[O:42])[C:9](=[O:11])[CH3:10])[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(OCCO)c(CN(C(C)=O)c2cc(F)ccc2Oc2ccccc2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(OCCOS(C)(=O)=O)c(CN(C(C)=O)c2cc(F)ccc2Oc2ccccc2)c1
Yield: 88 %

Procedure:
To a solution of 300 mg (0.71 mmol) 1e and 139 mg (1.06 mmol) diisopropyl ethyl amine in 5 ml dichloromethane was added 97 mg (0.85 mmol) mesyl chloride in 0.5 ml dichloromethane drop wisely at −10° C. The stirred reaction mixture was warmed over a period of 4 h to room temperature and diluted with dichloromethane. The organic phase was washed with saturated sodium hydrogen carbonate solution, water and brine. The organic phase was dried with magnesium sulfate. The crude product was purified by silica column chromatography (ethyl acetate:hexane gradient 1:6→1:2). The desired product 1f was obtained in 88% yield (346 mg, 0.62 mmol) as yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](O)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][CH:40]([OH:43])[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31].CC(OC(/N=N/C(OC(C)C)=O)=O)C>CCOC(C)=O.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1)[O:43][CH:40]1[CH2:41][CH2:42][N:37]([C:35]([O:34][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:36])[CH2:38][CH2:39]1
Reactant: COc1cc(O)cc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(Br)cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 0 °C

Procedure:
3-Bromo-5-methoxyphenol (0.18 g, 0.89 mmol) and triphenylphosphine (0.284, 1.07 mmol) were taken into THF (5 mL) and the resulting mixture cooled to 0° C. 4-Hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.18 g, 0.89 mmol), and DIAD (0.207 mL, 1.07 mmol) were taken up into THF (5 mL) and added slowly to the mixture, which was then stirred at room temperature over night. The resulting mixture was taken into EtOAc and washed with saturated NaHCO3 and brine. The solvent was dried over sodium sulfate and removed in vacuo. The resulting residue was purified on normal phase chromatography (EtOAc/heptane) to yield tert-butyl 4-(3-bromo-5-methoxyphenoxy)piperidine-1-carboxylate. MH+ 386.2, 388.2
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:14][C:15](N)=[O:16]>O>[O:16]=[C:15]1[NH:14][C:4](=[O:6])[C:3]2[C:2](=[CH:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][CH:7]=2)[NH:1]1
Reactant: Nc1cc(C(=O)O)ccc1C(=O)O
Reactant: NC(N)=O
Solvent: O
Product: O=C(O)c1ccc2c(=O)[nH]c(=O)[nH]c2c1
Temperature: 160 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
Into a round bottom flask was added 2-aminoterephthalic acid (0.83 g, 4.6 mmol) and urea (2.75 g, 45.8 mmol). The reaction mixture was heated to 160° C. and stirred overnight. The mixture was cooled to rt, water added and the solid was filtered. The solid was then washed with acetic acid to afford 2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid (0.87 g, 92%). LC-MS: (FA) ES+ 207.
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:15][C:16]([Cl:21])([Cl:20])[C:17](Cl)=[O:18]>C(Cl)Cl>[Cl:15][C:16]([Cl:21])([Cl:20])[C:17]([C:3]1[C:4]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[NH:10][C:2]=1[CH3:1])=[O:18]
Reactant: Cc1cc2ccncc2[nH]1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1[nH]c2cnccc2c1C(=O)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a stirred solution of 2-methyl-1H-pyrrolo[2,3-c]pyridine (2.5 g, 18.9 mmol) and aluminum chloride (5 g, 37.8 mmol) in DCM (100 mL), trichloroacetylchloride (4.1 g, 22.7 mmol) was added dropwise into the reaction over 0.5 hours at room temperature. After stirring 2 hours, the reaction was cooled to 0° C. and was quenched with water (100 mL). The resulting precipitate was isolated by filtration to afford 2,2,2-trichloro-1-(2-methyl-1H-pyrrolo[2,3-c]pyridin-3-yl)ethanone which was used for next step without further purification. Assumed 100% yield. (5.24 g).
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:20]=[CH:21][CH:22]=2)[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([OH:19])[CH:13]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2].F[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:20]=[CH:21][CH:22]=2)[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([O:19][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)[CH:13]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc([N+](=O)[O-])cc1

Procedure:
Using 3-(1-cyanocyclopropyl)-N-(3-hydroxy-4-methylphenyl)benzamide (1.46 g, 5.0 mmol), 1-fluoro-4-nitrobenzene (0.77 g, 5.5 mmol) and potassium carbonate (0.69 g, 5.0 mmol), and in the same manner as in Example A25(iii), the title compound (2.07 g, quantitatively) was obtained as a yellow oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:15])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4].O([CH2:24][CH3:25])S(C(F)(F)F)(=O)=O>C1COCC1.C(OCC)(=O)C>[CH2:24]([N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:7][C:6]([O:5][CH2:3][CH3:4])=[O:15])[CH3:25]
Reactant: CCOC(=O)CNc1ccccc1
Reactant: CCOS(=O)(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(CC)c1ccccc1
Reaction time: 1.5 h
Yield: 17.2 %

Procedure:
NaH (224 mg, 5.6 mmol of 60% dispersion) was washed 3 times with hexanes and dried via vacuum aspiration. To the dry NaH was added a solution of N-phenylglycine ethyl ester (1 g, 5.6 mmol) in THF (28 mL) at 0° C. After stirring 1.5 h, ethyl triflate (0.7 mL, 5.6 mmol) was added via syringe. The resulting solution was stirred at ambient temperature over 18 h. The mixture was diluted with ethyl acetate and washed with 1M HCl and brine. The organics were dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (4:1 hexanes/EtOAc) afforded the title compound as a light yellow oil (200 mg, 17%). MS (ES+) m/z 208 (MH+).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]1=[N:13][OH:14].C(=O)([O-])[O-].[Na+].[Na+].[Br:21][CH2:22][CH2:23]Br.O>CN(C)C=O>[CH3:1][O:2][N:3]=[C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]1=[N:13][O:14][CH2:23][CH2:22][Br:21]
Reactant: BrCCBr
Reactant: CON=C1C(=NO)Oc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CON=C1C(=NOCCBr)Oc2ccccc21
Yield: 70.7 %

Procedure:
1 g (0.0052 mol) of benzofuran-2,3-dione 3-(O-methyloxime) 2-oxime with 1.5 g (0.0141 mol) of sodium carbonate and 3 g (0.016 mol) of 1,2-dibromoethane in 5 ml of dimethylformamide are stirred at 80° C. for 6 hours. The reaction mixture is subsequently poured into water and extracted with diethyl ether. The organic phase is washed with aqueous potassium hydroxide solution and dried over sodium sulphate. The solvent is distilled off under reduced pressure, giving 1.1 g (70.7% of theory) of crude benzofuran-2,3-dione 2-[O-(2-bromoethyl)-oxime] 3-(O-methyloxime) as a mixture of stereoisomers which is reacted further without any purification.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][C:5]1[N:6]([CH3:24])[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([O:21][CH3:22])=[CH:10][CH:9]=2.C(N(CC)CC)C.Br[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]Br>CC(O)(C)C>[ClH:1].[CH3:22][O:21][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:23])[N:6]([CH3:24])[C:5]([CH2:4][CH2:3][N:2]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[C:14]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc2c(=O)n(C)c(CCN)c(-c3ccccc3)c2c1
Reactant: BrCCCCCBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: COc1ccc2c(=O)n(C)c(CCN3CCCCC3)c(-c3ccccc3)c2c1
Temperature: 150 °C
Reaction time: 24 h

Procedure:
To a solution of 3-(2-aminoethyl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one hydrochloride (100 mg, 0.290 mmol) in 15 mL of 2-methyl-2-propanol in a pressure tube was added triethylamine (0.142 mL, 1.02 mmol), followed by 1,5-dibromopentane (0.047 mL, 0.348 mmol). The mixture was heated at 150° C. overnight. Another portion of 1,5-dibromopentane was added (0.023 mL), and the heating continued for another 24 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by preparative reversed phase HPLC. The pure fractions were concentrated in vacuo, taken up in EtOAc and washed with saturated NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The product was taken up in dichloromethane, treated with excess ethereal HCl, and concentrated in vacuo to provide the HCl salt. Proton NMR for the product was consistent with the titled compound. ESI+MS: 377.19 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2].[CH:30]([NH:33][CH:34]([CH3:46])[CH2:35][CH2:36][O:37][C:38](=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([CH3:32])[CH3:31]>>[CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:33]([CH:30]([CH3:32])[CH3:31])[CH:34]([CH3:46])[CH2:35][CH2:36][O:37][C:38](=[O:45])[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[O:23])=[CH:24][CH:25]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCN(C)C[C@H]21
Reactant: CC(C)NC(C)CCOC(=O)c1ccccc1
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N(C(C)C)C(C)CCOC(=O)c3ccccc3)cc1)=N[C@@H]1CCN(C)C[C@H]21

Procedure:
Prepared from 4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]-naphthyridin-6-yl)benzoic acid and rac-benzoic acid 3-isopropylamino-butyl ester as described for example 1.