Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1)[CH2:27]Br>>[CH3:33][O:32][C:30]1[CH:29]=[C:26]([CH:25]=[C:24]([O:23][CH3:22])[CH:31]=1)[CH2:27][N:8]1[C:9]([C:10](=[O:19])[C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]1=[O:20]
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: COc1cc(CBr)cc(OC)c1
Product: COc1cc(Cn2c(C(=O)c3cc(C)cc(C)c3)c(C(C)C)c(=O)[nH]c2=O)cc(OC)c1
Yield: 67.8 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 3,5-dimethoxybenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (296 mg, yield: 67.8%).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.N([O:14][CH2:15][CH2:16][CH:17]([CH3:19])C)=O>O1C=CC=C1>[O:14]1[CH:15]=[CH:16][CH:17]=[C:19]1[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1
Reactant: Cc1nc2cc(N)ccc2o1
Reactant: CC(C)CCON=O
Solvent: c1ccoc1
Product: Cc1nc2cc(-c3ccco3)ccc2o1
Temperature: 30 °C
Yield: 43 %

Procedure:
5-Amino-2-methylbenzoxazole (7.0 g, 0.05 mole), isopentyl nitrite (20 mL), and furan (230 mL) were combined and heated with stirring at 30° C. in a roundbottom flask equipped with a condenser. After heating for 48 hrs, the reaction mixture was removed from the heat, washed with water, and then evaporated to an oil. Distillation afforded the product (4.0 g, 43% yield), bp 130°-140° C. (0.6 mm). Recrystallization from isopropyl alcohol (14 mL) afforded 3.0 g (32% yield), mp 60° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[C:12]([CH:15]2[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]2)[CH2:13][CH3:14])=[CH:7][CH:6]=1.[CH3:29][NH2:30]>CO>[OH:21][CH:18]1[CH2:19][CH2:20][CH:15]([C:12]([CH2:13][CH3:14])=[C:11]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:30][CH3:29])=[CH:6][CH:7]=2)[CH2:16][CH2:17]1
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)C1CCC(O)CC1
Reactant: CN
Solvent: CO
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCNC)cc1)C1CCC(O)CC1
Yield: 3 %

Procedure:
Following the same procedure as described in example 11, step D, 4-(1-(4-(2-chloroethoxy)phenyl)-2-(4-hydroxycyclohexyl)but-1-enyl)phenol (0.8 g, 1.0 eq) was reacted with MeNH2 (30% wt in water, 10 mL) in MeOH (20 mL) at reflux to give 20 mg desired product (3% yield, Z/E=1/1). 1H NMR (400 MHz, CDCl3) δ 7.03 (d, J=8.4 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 6.78 (d, J=8.4 Hz, 2H), 6.71 (d, J=8.4 Hz, 2H), 4.04 (t, J=4.8 Hz, 2H), 2.96 (t, J=4.8 Hz, 2H), 2.50 (s, 3H), 2.36-2.47 (m, 1H), 2.04 (q, J=7.6 Hz, 2H), 1.90-2.01 (m, 2H), 1.40-1.80 (m, 6H), 0.87 (t, J=7.6 Hz, 3H); m/z=396[M+1]+.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1OC>>[CH:6]([C:5]1[CH:8]=[CH:9][CH:2]=[CH:3][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH2:7]
Reactant: COc1ccccc1Br
Reactant: C=Cc1ccc(Br)cc1
Product: C=Cc1ccccc1-c1ccccc1

Procedure:
A vinylbiphenyl polymer was prepared in the same manner as in Example 10 except that poly-p-bromostyrene obtained as in Example 10 by using p-bromostyrene instead of p-chlorostyrene, and o-bromoanisol were used. The polymer gave a peak of OCH3 through 1H-NMR measurement in the same manner as in Example 10.
Reaction SMILES: C1(C)C=CC(S(OCC[N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])(=O)=O)=CC=1.[I-].[K+].C(=O)([O-])O.[Na+]>CN(C)C=O>[C:17]1(=[O:18])[NH:13][C:14](=[O:23])[C:15]2=[CH:22][CH:21]=[CH:20][CH:19]=[C:16]12
Reactant: Cc1ccc(S(=O)(=O)OCCN2C(=O)c3ccccc3C2=O)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccccc21
Yield: 113.7 %

Procedure:
Compound 45 (500 mg) obtained in Example 1, N-{2-(p-toluenesulfonyloxy)ethyl}phthalimide (537 mg), potassium iodide (258 mg), and sodium hydrogen carbonate (131 mg) were stirred in dimethylformamide (8 ml) at 150° C. for 28 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 260 mg of phthalimide compound.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][S:11][C:5]=2[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:3]1.N1C=CC=CC=1.[C:24]12([CH2:34][C:35](Cl)=[O:36])[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2>C(Cl)Cl.CCOC(C)=O>[C:24]12([CH2:34][C:35]([NH:1][N:2]3[C:7](=[O:8])[C:6]4[CH:9]=[CH:10][S:11][C:5]=4[C:4]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:3]3)=[O:36])[CH2:31][CH:30]3[CH2:29][CH:28]([CH2:27][CH:26]([CH2:32]3)[CH2:25]1)[CH2:33]2
Reactant: Nn1nc(-c2ccccc2)c2sccc2c1=O
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nn1nc(-c2ccccc2)c2sccc2c1=O
Reaction time: 2 h
Yield: 51.8 %

Procedure:
A mixture of the product from Example 9B (31 mg), pyridine (0.012 mL, 0.15 mmol), and (adamantan-1-yl)acetyl chloride (31 mg, 0.15 mmol) in CH2Cl2 (0.4 mL) was stirred for 2 hours, diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), and filtered. The residue was chromatographed on SiO2 (10% EtOAc/CH2Cl2) to give the title compound (27.7 mg, 0.066 mmol) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 11.31 (s, 1H), 8.23 (d, J=5.2 Hz, 1H), 7.86-7.78 (m, 3H), 7.65-7.55 (m, 3H), 2.07 (s, 2H), 1.95 (s, 3H), 1.76-1.53 (m, 12H); MS (ESI+) M/Z 420.3 (M+H)+.
Reaction SMILES: I[C:2]1[C:7]2[C:8]3[C:9]([NH:15][C:6]=2[C:5](=[O:16])[N:4]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:3]=1)=[N:10][CH:11]=[C:12]([CH3:14])[CH:13]=3.[CH2:26]([S:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29])[CH3:27].O1CCOCC1>C(Cl)Cl>[CH2:26]([S:28]([C:31]1[CH:36]=[C:35]([C:2]2[C:7]3[C:8]4[C:9]([NH:15][C:6]=3[C:5](=[O:16])[N:4]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH:3]=2)=[N:10][CH:11]=[C:12]([CH3:14])[CH:13]=4)[CH:34]=[CH:33][CH:32]=1)(=[O:29])=[O:30])[CH3:27]
Reactant: CCS(=O)(=O)c1cccc(B(O)O)c1
Reactant: COc1ccc(Cn2cc(I)c3c([nH]c4ncc(C)cc43)c2=O)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1cccc(-c2cn(Cc3ccc(OC)cc3)c(=O)c3[nH]c4ncc(C)cc4c23)c1
Temperature: 150 °C

Procedure:
In an appropriate microwave reaction vessel was placed, 5-iodo-7-(4-methoxybenzyl)-3-methyl-7,9-dihydro-8H-pyrido[4′,3′:4,5]pyrrolo[2,3-b]pyridin-8-one (8.0 g, 17.967 mmol), 3-(ethylsulfonyl)phenyl boronic acid (4.62 g, 21.6 mmol), and Tetrakis(triphenylphosphine)Pd(0) (6.23 g, 5.4 mmol). The solids were then suspended in a dioxane/saturated K2CO3 solution (40.0 mL, 4/1) and the mixture was heated in a large scale CEM microwave for 20 minutes at 150° C. The reaction mixture was diluted with DCM (400 mL), then filtered off undissolved solids. The organic layer was washed with brine (300 mL), dried with MgSO4, filtered and concentrated in vacuo affording an orange solid. The crude solid was washed with a hot ethyl acetate/hexanes solution (400 mL, 1/1) followed by a hot ethanol/DCM solution (400 mL, 4/1). The product was isolated by filtration, washed with ether and dried under vacuum affording an off-white solid. (6.83 g, 78%) 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36 (t, J=7.45 Hz, 3H) 2.44 (s, 3H) 3.20 (q, J=7.33 Hz, 2H) 3.80 (s, 3H) 5.37 (s, 2H) 6.90 (d, J=8.59 Hz, 2H) 7.16 (s, 1H) 7.37 (d, J=8.59 Hz, 3H) 7.75 (t, J=7.71 Hz, 1H) 7.78-7.87 (m, 2H) 8.03 (d, J=7.58 Hz, 1H) 8.12 (s, 1H) 8.43 (s, 1H). ESI-MS: m/z 488.3 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]#[N:29])=[CH:18][CH:17]=3)[C:7]3=[N:8][CH:9]=[C:10](Br)[C:11]([CH3:12])=[C:6]3[N:5]=2)[CH2:3][CH2:2]1.C(O)=O.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:1]1([C:4]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]#[N:29])=[CH:18][CH:17]=3)[C:7]3=[N:8][CH:9]=[CH:10][C:11]([CH3:12])=[C:6]3[N:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(Br)cnc2c1nc(C1CC1)n2Cc1ccc(-c2ccccc2C#N)cc1
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccnc2c1nc(C1CC1)n2Cc1ccc(-c2ccccc2C#N)cc1
Yield: 78 %

Procedure:
Toluene (30 ml) was added to 2.0 g (4.5 mmol) of 2-cyclopropyl-3-(2'-cyanobiphenyl-4-yl)methyl-6-bromo-7-methyl-3H-imidazo[4,5-b]pyridine, 1.24 g (27.0 mmol) of formic acid, 4.55 g (45.0 mmol) of triethylamine and 10% Pd--C (100 mg), followed by heating under reflux for 6 hours. After the reaction liquid was brought to room temperature and filtered to remove the catalyst, vacuum concentration was effected. Chloroform (50 ml) and water (50 ml) were added to the residue and the obtained mixture was caused liquid-liquid separation. The aqueous phase was further extracted with chloroform (30 ml) twice. The organic phases were combined, dried over anhydrous magnesium sulfate and subjected to vacuum concentration. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 1.28 g of 2-cyclopropyl-3-(2'-cyanobiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine (yield 78%).
Reaction SMILES: [C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[NH4+:9].[C:10]([OH:22])(=[O:21])[CH2:11][C:12]([CH2:17][C:18]([OH:20])=[O:19])([C:14]([OH:16])=[O:15])[OH:13].[Al].[OH-].[Na+]>>[NH2:9][C@H:2]([C:1]([OH:8])=[O:7])[CH2:3][C:4]([OH:6])=[O:5].[C:10]([OH:22])(=[O:21])[CH2:11][C:12]([CH2:17][C:18]([OH:20])=[O:19])([C:14]([OH:16])=[O:15])[OH:13]
Reactant: [NH4+]
Reactant: O=C([O-])/C=C\C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Al]
Agent: [Na+]
Product: N[C@@H](CC(=O)O)C(=O)O

Procedure:
Monoammonium maleate (2,627 g of 94% concentration wet salt, 0.0186 mole) and citric acid (0,395 g, 0.0021 mole) were ground together and thoroughly mixed to form a slightly wetted mass. This mixture was placed in the aluminum reaction vessel to form a layer and then was heated at about 240°-260° C. for 40 minutes in a convection oven. The resulting product was a red-brown solid foam, weight 1.991 g, representing 92% theoretical yield of polysuccinimidecitric acid copolymer. Hydrolysis of this product with sodium hydroxide at room temperature produced an aspartic acid-citric acid copolymer having molecular weights by GPC of Mw 1196, Mn 613, Mw/Mn 1.95.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][O:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4][CH:3]1C(OC)=O.CO.Cl>O>[O:1]=[C:2]1[CH2:3][O:4][C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[O:7][CH2:8]1
Reactant: COC(=O)C1Oc2ccccc2OCC1=O
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C1COc2ccccc2OC1

Procedure:
3-Oxo-4-carbomethoxy-3,4-dihydro-2H-1,5-benzodioxepin (110 g.) is added to a mixture of methanol (210 ml.), concentrated hydrochloric acid (50 ml.) and water (160 ml.) and the mixture then is refluxed for 18 hours. The product is extracted with ether, and the ether extract washed with four 50 ml. portions of sodium bicarbonate solution, then twice with 50 ml. portions of water. After drying the washed ether extract over magnesium sulfate and evaporation to remove the solvent there is obtained 3-oxo-3,4-dihydro-2H-1,5-benzodioxepin.
Reaction SMILES: [CH2:1]([NH:6][C:7]([C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:16]([N:23]1[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CC([O-])(C)C.[K+]>O1CCOCC1>[CH2:1]([NH:6][C:7]([C:9]1[N:10]=[N:11][C:12]([O:29][CH:26]2[CH2:27][CH2:28][N:23]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:24][CH2:25]2)=[CH:13][CH:14]=1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: CCCCCNC(=O)c1ccc(Cl)nn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCCCCNC(=O)c1ccc(OC2CCN(Cc3ccccc3)CC2)nn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28 %

Procedure:
To a mixture of 6-chloropyridazine-3-carboxylic acid pentylamide (0.530 g, 2.33 mmol) and 1-benzylpiperidin-4-ol (0.399 g, 2.33 mmol) in dioxane (20 mL) was added KOtBu (0.288 g, 2.56 mmol). The colourless reaction mixture turned to bright red upon the addition of KOtBu. The reaction mixture was stirred at room temperature for 16 hours, then concentrated in vacuo. The residue was diluted with ethyl acetate, washed with water, dried over Na2SO4, filtered and concentrated. The crude material was purified by column chromatography to afford the title compound in 28% yield (0.100 g). The solid material was triturated with ether give 22.7 mg of product as a colourless solid. M.p. 127-130° C. 1H NMR (300 MHz, CDCl3) δ 8.15 (d, J=9.3 Hz, 1H), 7.91 (t, J=5.1 Hz, 1H), 7.31 (m, 5H), 7.02 (d, J=9.3 Hz, 1H), 5.34 (septet, J=4.5 Hz, 1H), 3.51 (s, 2H), 3.44 (q, J=6.9 Hz, 2H), 2.79-2.73 (m, 2H), 2.35-2.27 (m, 2H), 2.15-2.09 (m, 2H), 1.93-1.83 (m, 2H), 1.62-1.54 (m, 2H), 1.36-1.29 (m, 4H), 0.89-0.85 (m, 3H). 13C NMR (75 MHz, CDCl3) δ 165.9, 162.5, 148.6, 138.4, 129.6, 129.1, 128.7, 128.3, 127.1, 118.6, 73.8, 62.9, 50.8, 39.5, 30.8, 29.2, 29.1, 22.4, 14.0. MS (ES+) m/z 363 (M+1).
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:5])=[N+]=[N-].CP(C)C>O1CCCC1>[F:21][C:17]1[CH:16]=[C:15]([N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[C:6]2[CH:4]([NH2:1])[CH3:5])[CH:20]=[CH:19][CH:18]=1
Reactant: CC(N=[N+]=[N-])c1cc2ccccc2n1-c1cccc(F)c1
Agent: CP(C)C
Solvent: C1CCOC1
Product: CC(N)c1cc2ccccc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 133.7 %

Procedure:
To a solution of 2-(1-azidoethyl)-1-(3-fluorophenyl)-1H-indole (0.14 g, 0.50 mmol) in tetrahydrofuran (3 mL) was added 1.00 M trimethylphosphine in tetrahydrofuran (0.75 mL, 0.75 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated to give crude product (0.17 g), which was used directly in the next step. LCMS calculated for C16H13FN(M-NH2)+: m/z=238.1. Found: 238.1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[O:19][CH3:20].[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[C:25]=1[N:33]=[C:34]=[O:35])([CH3:23])[CH3:22]>>[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:31])[CH3:32])[C:25]=1[NH:33][C:34](=[O:35])[N:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([O:19][CH3:20])[CH:4]=1)[C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=1)([CH3:22])[CH3:23]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: COc1cc(CNc2ccc(C(C)C)cc2)ccc1O
Product: COc1cc(CN(C(=O)Nc2c(C(C)C)cccc2C(C)C)c2ccc(C(C)C)cc2)ccc1O

Procedure:
By the reaction and treatment in the same manner as in Example 2 using (4-hydroxy-3-methoxyphenylmethyl)(4-isopropylphenyl)amine (7.0 g) and 2,6-diisopropylphenyl isocyanate (5.5 mL) as starting materials, N′-(2,6-diisopropylphenyl)-N-[(4-hydroxy-3-methoxyphenyl)methyl]-N-(4-isopropylphenyl)urea (0.65 g) was obtained.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12]([Mg]Cl)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C1COCC1.CN1C(=O)CCC1>[CH2:25]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: COC(=O)c1ccc(Cl)cc1
Reactant: CCCCCCCCCCCCCC[Mg]Cl
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCc1ccc(C(=O)OC)cc1
Reaction time: 0.05 h
Yield: 92 %

Procedure:
To a solution of methyl 4-chlorobenzoate (300 mg, 1.76 mmol) and Fe(acac)3 (71 mg, 0.2 mmol) in THF (7 mL) and NMP (1.1 mL) at −60° C. is added a solution of C14H29MgCl (1M in THF, 2.3 mL). The mixture immediately turns black and becomes viscous after 3 min. Work-up as described above provides methyl 4-(tetradecyl)benzoate as a low-melting solid (92%). Mp=28–29° C. 1H NMR (300 MHz, CDCl3): δ 7.92 (dd, 2H, J=6.5, 1.8 Hz), 7.21 (dd, 2H, J=6.4, 1.7 Hz), 3.87 (s, 3H), 2.63 (t, 2H, J=7.7 Hz), 1.60 (m, 2H), 1.38–1.06 (m, 24H), 0.86 (t, 3H, J=6.7 Hz). 13C NMR (75 MHz, CDCl3): δ 167.6, 148.9, 130.0, 128.8, 128.0, 52.3, 36.4, 32.3, 31.5, 30.09, 30.07, 30.05, 30.00. 29.95, 29.9, 29.8, 29.7, 23.1, 14.5. IR: 3091, 3061, 3031, 2925, 2854, 1726, 1611, 1574, 1510, 1466, 1435, 1415, 1377, 1309, 1277, 1191, 1178, 1109, 1021, 970, 854, 763, 722, 704 cm−1. MS m/z (rel. intensity) 332 (100, [M+]), 301 (1), 163 (34), 150 (60), 149 (29).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[CH:10]=[CH:11][O:12][C:4]=2[CH2:3]1.F[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1>>[CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([O:9][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[C:5]2[CH:10]=[CH:11][O:12][C:4]=2[CH2:3]1
Reactant: Fc1ccc2ccccc2c1
Reactant: CN1CCC(O)c2ccoc2C1
Product: CN1CCC(Oc2ccc3ccccc3c2)c2ccoc2C1

Procedure:
The same method as in Example 1 was conducted using 7-methyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 19) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2-fluoronaphthalene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [CH2:1]([C:3]1([CH:16]=[O:17])[CH2:15][CH:6]2[CH2:7][N:8]([C:10]([N:12]([CH3:14])[CH3:13])=[O:11])[CH2:9][CH:5]2[CH2:4]1)[CH3:2].O.O.P([O-])(O)(O)=[O:21].[Na+].Cl([O-])=O.[Na+].CC(=CC)C>O1CCCC1.O>[CH2:1]([C:3]1([C:16]([OH:21])=[O:17])[CH2:15][CH:6]2[CH2:7][N:8]([C:10](=[O:11])[N:12]([CH3:13])[CH3:14])[CH2:9][CH:5]2[CH2:4]1)[CH3:2]
Reactant: CCC1(C=O)CC2CN(C(=O)N(C)C)CC2C1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1CCOC1
Solvent: O
Product: CCC1(C(=O)O)CC2CN(C(=O)N(C)C)CC2C1
Yield: 99.7 %

Procedure:
5-Ethyl-5-formyl-N,N-dimethyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 19b (0.4 g, 1.68 mmol) was dissolved in the solvent mixture of 18 mL of tetrahydrofuran and 9 mL of water, followed by addition of sodium dihydrogenphosphate dihydrate (787 mg, 5.04 mmol), sodium chlorite (0.454 g, 5.04 mmol) and 2-methyl-2-butene (354 mg, 5.06 mmol) at 0° C. The reaction mixture was reacted at 0° C. for 2 hours under nitrogen atmosphere. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound 5-ethyl-2-dimethylcarbamoyl-hexahydro-cyclopenta[c]pyrrole-5-carboxylic acid 19c (0.426 g, yield 100%) as a yellow solid which was directly used in the next step.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[CH3:14][N:15]([CH3:17])[CH:16]=[CH:2][C:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc(C(=O)O)s1
Reactant: COC(OC)N(C)C
Product: CN(C)C=CC(=O)c1ccc(C(=O)O)s1
Temperature: 120 °C

Procedure:
5-Acetyl-thiophene-2-carboxylic acid (1 g, 5.87 mmol) was treated with N,N-dimethylformamide dimethylacetal (10 mL) and heated at 120° C. for 16 hours. The mixture was dried in vacuo to give 5-(3-dimethylamino-acryloyl)thiophene-2-carboxylic acid which was taken to the next step. MS: m/z 226 (M+H+).
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]2[NH:20][C:21]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH2:30])[N:25]=3)=[C:22]([I:23])[C:16]=2[C:15]1=[O:31])=[O:13])([CH3:10])([CH3:9])[CH3:8].CI.O>CN(C=O)C.C(Cl)Cl>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]2[N:20]([CH3:1])[C:21]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH2:30])[N:25]=3)=[C:22]([I:23])[C:16]=2[C:15]1=[O:31])=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c(-c3ccnc(N)n3)c(I)c2C1=O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CI
Solvent: ClCCl
Product: Cn1c2c(c(I)c1-c1ccnc(N)n1)C(=O)N(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.4 %

Procedure:
Cesium carbonate (2.17 g, 6.68 mmol) was added to a solution of 2-(2-amino-pyrimidin-4-yl)-3-iodo-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (1.38 g, 3.03 mmol) in DMF (60 mL) and the mixture was stirred at room temperature for 1 h. Methyl iodide (0.948 g, 6.68 mmol) was then added and after 2 h stirring at room temperature, water (0.100 mL) and DCM (0.100 mL) were poured into the reaction vessel. The organic layer was separated, dried over Na2SO4, and concentrated under vacuum to yield the crude 2-(2-amino-pyrimidin-4-yl)-3-iodo-1-methyl-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester as a brown solid (0.854 g, 1.8 mmol, 60%).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH2:22][C:23]([O:25]C)=[O:24])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:27]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[OH-].[Li+]>>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH2:22][C:23]([OH:25])=[O:24])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:27]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2
Agent: [Li+]
Agent: [OH-]
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(CC(=O)O)cc1OCC2

Procedure:
Methyl 2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acetate and lithium hydroxide were reacted to give 336. M/z 354.1, calc. 353.15
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([F:12])[CH:6]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:7]([F:12])[CH:6]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)Cc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(OCc2ccccc2)c(F)c1
Temperature: 60 °C
Yield: 86.6 %

Procedure:
To a solution of (3-fluoro-4-hydroxy-phenyl)-acetic acid methyl ester (15 g, 54.3 mmol) and benzyl bromide (9.28 g, 54.3 mmol) in DMF (50 mL), was K2CO3 (7.24 g, 54.3 mmol) added at an ambient temperature. The reaction mixture was heated to 60° C. and maintained for 2 hours. The reaction was cooled to room temperature and poured into H2O (150 mL). The organic compound was extracted with ether (150 mL) and washed with sat NaHCO3 (100 mL). The ether layer was dried over MgSO4, and concentrated under vacuum to afford the desired compound (12.9 g, 87.9%) as a white crystal. The crude compound was used for the next step without further purification. 1H NMR (400 Mz, DMSO-d6) δ 7.41-7.49 (m, 5H), 7.15-7.23 (m, 2H), 7.02-7.04 (m, 1H), 5.19 (s, 2H), 3.65 (s, 2H), 3.63 (s, 3H). LCMS 273.4 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])O[C:7](=[O:12])[C:6]=2[CH:13]=1.[CH3:14][O:15][C:16]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:17]=1[CH2:18][NH:19][CH2:20]C(O)=O>CC1C=CC(C)=CC=1>[CH3:14][O:15][C:16]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:17]=1[CH2:18][N:19]1[C:7](=[O:12])[C:6]2[CH:13]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[NH:10][C:9](=[O:11])[CH2:20]1
Reactant: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Reactant: COc1ccc(CNCC(=O)O)c(OC)c1
Solvent: Cc1ccc(C)cc1
Product: COc1ccc(CN2CC(=O)Nc3ccc(Br)cc3C2=O)c(OC)c1
Temperature: 150 °C

Procedure:
A suspension of 6-bromo-2H-3,1-bezoxazine-2,4(1H)-dione (22.0 g, 91 mmol) containing (2,4-dimethoxy-benzylamino)-acetic acid (22.5 g, 100 mmol) in p-xylene (200 mL) was heated under reflux (150° C.) for 1 h. After cooling to room temperature the precipitate was filtered off and washed with p-xylene (100 ml). Yield: 33.5 g (91%) m/z 403/405 (M).