Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][B:2]1[C:6](=[CH:7][C:8]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:15]=2[CH3:23])(=[O:13])=[O:12])=[CH2:9])[CH2:5][CH2:4][O:3]1.[CH3:24]O>[Pd]>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([S:11]([NH:10][C:8]2[CH:9]=[CH:24][C:5]3[CH2:4][O:3][B:2]([OH:1])[C:6]=3[CH:7]=2)(=[O:13])=[O:12])=[C:15]([CH3:23])[CH:16]=1
Reactant: CO
Reactant: C=C(C=C1CCOB1O)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1C
Agent: [Pd]
Product: Cc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Reaction time: 1 h
Yield: 15 %

Procedure:
A mixture of N-[1-(2-hydroxy-[1,2]oxaborolan-3-ylidenemethyl)-vinyl]-2-methyl-4-nitro-benzenesulfonamide (300 mg, 0.86 mmol) and Pd/C (300 mg, 10% wet) in MeOH (20.0 mL) was placed under a hydrogen atmosphere at 50 psi at rt for 1 h. The solid catalyst was filtered off through a pad of Celite. The filtrate was then concentrated in vacuo and the residue was suspended in hot water. The solid product was filtered and dried to affording 40 mg (15%) of the title compound as a white solid. mp. 174-175° C.; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.90 (br. s., 1H), 9.15 (s, 1H), 7.51 (d, J=8.2 Hz, 1H), 7.40 (d, J=1.6 Hz, 1H), 7.21-7.16 (m, 1H), 7.14-7.09 (m, 1H), 6.34-6.28 (m, 2H), 5.81 (s, 2H), 4.83 (s, 2H), 2.38 (s, 3H); (ESI) m/z=317 (M−1, negative); HPLC purity: 96.23% (MaxPlot 200-400 nm), 97.5% (220 nm).
Reaction SMILES: O[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:19](=O)[CH3:20].[NH2:22][NH2:23]>C(O)COCCO>[CH3:20][C:19]1[C:3]2[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=3[C:10]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[CH:11][C:2]=2[NH:23][N:22]=1
Reactant: CC(=O)c1c(O)cc(-c2ccc(O)cc2)c2ccccc12
Reactant: NN
Solvent: OCCOCCO
Product: Cc1n[nH]c2cc(-c3ccc(O)cc3)c3ccccc3c12
Reaction time: 2 h
Yield: 60.1 %

Procedure:
A solution of 1-[2-hydroxy-4-(4-hydroxyphenyl)napthalen-1-yl]ethanone (0.223 g, 0.8 mmol), and 35% aqueous hydrazine (0.72 mL, 8.0 mmol) in diethylene glycol (2.7 mL) was heated using a reflux condenser in a 170° C. oil bath for 12 h, then 190° C. for 2 h until 95% complete conversion was observed. The crude solution was purified directly via preparative reverse phase HPLC (CH3CN/H2O/TFA eluent) to give 0.132 g (60% yield) of 4-(1-methyl-3H-benzo[e]indazol-5-yl)phenol. 1H NMR (400 MHz, d6-DMSO): 9.62 (broad s, 1H), 8.37 (d, 1H), 7.82 (d, 1H), 7.65 (dt, 1H), 7.42 (dt, 1H), 7.39 (s, 1H), 7.30 (dd, 2H), 6.93 (s, 2H), 2.82 (s, 3H); MS (EI) for C18H14N2O: 275 (MH+).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]([NH2:13])[C:8]2([CH3:12])[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.C([O:16][C:17]1[C:20](=[O:21])[C:19](=O)[C:18]=1[NH:23][C:24]1[C:25]([OH:40])=[C:26]([CH:37]=[CH:38][CH:39]=1)[C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@@H:30]1[C:34]([OH:36])=[O:35])=[O:28])C>CO.C(OCC)C>[OH:40][C:25]1[C:24]([NH:23][C:18]2[C:17](=[O:16])[C:20](=[O:21])[C:19]=2[NH:13][CH:7]([C:5]2[O:6][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:8]2([CH3:12])[CH2:9][O:10][CH2:11]2)=[CH:39][CH:38]=[CH:37][C:26]=1[C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@@H:30]1[C:34]([OH:36])=[O:35])=[O:28]
Reactant: CCOc1c(Nc2cccc(C(=O)N3CCC[C@@H]3C(=O)O)c2O)c(=O)c1=O
Reactant: Cc1ccc(C(N)C2(C)COC2)o1
Solvent: CCOCC
Solvent: CO
Product: Cc1ccc(C(Nc2c(Nc3cccc(C(=O)N4CCC[C@@H]4C(=O)O)c3O)c(=O)c2=O)C2(C)COC2)o1
Reaction time: 72 h
Yield: 58.6 %

Procedure:
494 mg (2.73 mmol) of C-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine in 3 ml of methanol were added to a solution of 500 mg (1.34 mmol) of (R)-1-[3-(2-ethoxy-3,4-dioxocyclobut-1-enylamino)-2-hydroxy-benzoyl]pyrrolidine-2-carboxylic acid in 47 ml of methanol at 50° C. After 3 days, 248 mg (1.37 mmol) of C-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine were added. After 4 days, the reaction medium was concentrated to dryness. The reaction medium was taken up in ethyl acetate and was washed with a saturated aqueous ammonium chloride solution and then with a 1 M aqueous solution of sodium dihydrogen phosphate. The organic phase was dried over magnesium sulfate, filtered and concentrated. The solid obtained was taken up, with stirring, in diethyl ether and a little ethyl acetate and was filtered. 400 mg of a beige solid were obtained. This solid was chromatographed on silica gel (ethyl acetate/acetone/water: 50/50/2 then 50/50/5). 240 mg were obtained in the form of a beige solid. Yield=35%, HPLC=52.43%+45.15% (mixture of the two diastereoisomers), Mp=198-205° C.
Reaction SMILES: C(OC(=O)[NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16]C(=O)C)[CH:12]=2)[C:7]=1[Cl:20])C.[OH-].[K+]>C(O)C>[Cl:20][C:7]1[C:8]2[C:13](=[CH:12][C:11]([OH:16])=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:6]=1[NH2:5]
Reactant: CCOC(=O)Nc1ccc2cc(OC(C)=O)ccc2c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc2cc(O)ccc2c1Cl

Procedure:
A mixture of N-(6-acetyloxy-1-chloro-2-naphthyl)carbamic acid ethyl ester (375 mg, 1.34 mmol) and KOH (903 mg, 16.1 mmol) in ethanol (10 mL) is heated to reflux temperature under N2 atmosphere for 4.5 hours. The reaction mixture is concentrated by rotary evaporator under high vacuum. The residual oil is partitioned between EtOAc and water. After acidification (2 N HCl), the organic layer is separated, washed with brine and dried (MgSO4). Concentration by rotary evaporator gives 1-chloro-2-amino-6-naphthol as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]([C:16]2[NH:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)[OH:15])[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[O:15])[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(C(O)c2nc3ccccc3[nH]2)cc([N+](=O)[O-])c1OC
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1cc(C(=O)c2nc3ccccc3[nH]2)cc([N+](=O)[O-])c1OC

Procedure:
13.2 g of α-(3,4-dimethoxy-5-nitro-phenyl)-2-benzimidazolemethanol are dissolved in 200 ml of methylene chloride and, after treatment with 130 g of manganese dioxide, the mixture is stirred at the reflux temperature for 2 hours. After filtration, the solvent is distilled. There is obtained 2-benzimidazolyl (3,4-dimethoxy-5-nitrophenyl) ketone in the form of yellowish crystals of m.p. 212°-213°.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[OH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(=O)([O-])O.[Na+]>C1COCC1>[OH:29][CH:30]1[CH2:35][CH2:34][N:33]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][C:16]([C:22]5[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=5)=[CH:17][CH:18]=4)[CH:13]=3)=[O:11])=[CH:5][CH:4]=2)[CH2:32][CH2:31]1
Reactant: OC1CCNCC1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN4CCC(O)CC4)cc2)CC3)cc1
Temperature: 25 °C
Yield: 77.4 %

Procedure:
In THF (10 ml) was dissolved N-[4-(chloromethyl)phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (300 mg), and to the mixture was added 4-hydroxypiperidine (235 mg). The mixture was refluxed for 24 hours. The reaction mixture was cooled to room temperature, and to the mixture was added 5% sodium hydrogen carbonate solution (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give N-[4-(4-hydroxypiperidinomethyl)phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (Compound 49) (271 mg) as colorless crystals.
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[CH3:6][Si:7]([C:10]#[CH:11])([CH3:9])[CH3:8]>ClCCl.[Zn+2].[I-].[I-].C1(P(CC)C2C=CC=CC=2)C=CC=CC=1>[CH3:6][Si:7]([CH3:9])([CH3:8])[C:10]1[CH2:11][CH:5]=[C:3]([CH3:4])[CH2:2][CH:1]=1
Reactant: C=CC(=C)C
Reactant: C#C[Si](C)(C)C
Agent: CCP(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC1=CCC([Si](C)(C)C)=CC1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
In a four-necked flask, 1.12 g (5.1 mmol) of CoBr2, 5.43 g (17 mmol) of ZnI2, and 2.24 g (5.6 mmol) of diphenylphosphinoethane were dissolved in 250 ml of dichloromethane, and the solution was stirred for 30 minutes at 30° C. Subsequently, 50 ml (500 mmol) of isoprene, 63.5 ml (450 mmol) of trimethylsilylacetylene, and 1.45 g (5.6 mmol) of Bu4NBH4 were added thereto, and the mixture was allowed to react for one hour at 30° C. After completion of the reaction, dichloromethane was evaporated, and then the residue was distilled under reduced pressure. Thus, 68.6 g of the title compound, trimethyl (4-methyl-1,4-cyclohexadienyl) silane, was obtained at a yield of 91.7% (GC purity 80%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:13])/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].[C:14](O)(=[O:34])[CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH3:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC#N.CCOC(C)=O>[C:14]([NH:2][CH2:3][CH2:4][NH:5][C:6](=[O:13])/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10])(=[O:34])[CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32][CH3:33]
Reactant: COC(=O)/C=C/C(=O)NCCN
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)NCCNC(=O)/C=C/C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
The HCl salt of (E)-methyl 4-(2-aminoethylamino)-4-oxobut-2-enoate (0.735 mmol) was taken up in 40 mL of CH3CN along with (5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenoic acid (EPA, 222 mg, 0.735 mmol), HATU (307 mg, 0.81 mmol) and DIEA (380 μL). The resulting reaction mixture was stirred at room temperature for 2 h and diluted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3, brine, dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography (95% CH2Cl2, 5% MeOH) afforded 300 mg of (E)-methyl 4-(2-(5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenamidoethylamino)-4-oxobut-2-enoate (89% yield). MS (EI) calcd for C27H40N2O4: 456.3. found: 457 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[C:10]([NH2:18])=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=1)[CH3:20].C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C>ClCCl>[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([NH:18][C:10]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=2[NH:8][CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[O:30])=[CH:24][CH:23]=1)[CH3:20]
Reactant: CN1CCC(Nc2ccc([N+](=O)[O-])cc2N)CC1
Reactant: CCOc1ccc(CC(=O)O)cc1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: ClCCl
Product: CCOc1ccc(CC(=O)Nc2cc([N+](=O)[O-])ccc2NC2CCN(C)CC2)cc1
Temperature: 25 °C

Procedure:
N1-(1-Methyl-piperidin-4-yl)-4-nitro-benzene-1,2-diamine 52 (0.330 g, 1.318 mmol) was dissolved in anhydrous dichloromethane (15 mL) in a small, argon purged flask fitted with an condenser and magnetic stirbar. (4-Ethoxy-phenyl)-acetic acid 5 (0.249 g, 1.384 mmol) followed by 2-Ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (0.391 g, 1.582 mmol) are added quickly as solids and resulting solution heated to reflux for 14 hours. After cooling to room temperature the solvent was removed under reduced pressure and the resulting residue partitioned between H2O and chloroform and 2M ammonium hydroxide solution added to adjust pH to 10. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with chloroform and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered and concentrated to afford crude. Recrystallization of the crude from ethyl acetate yielded a yellow solid 53 2-(4-Ethoxy-phenyl)-N-[2-(1-methyl-piperidin-4-ylamino)-5-nitro-phenyl]-acetamide. Yield: 0.200 grams (36.8%). 1H NMR (DMSO) δ: 1.31 (t, 3H, J=6.9), 1.41-1.56 (m, 2H), 1.86-1.89 (m, 2H), 1.99-2.07 (m, 2H), 2.17 (s, 3H), 2.69-2.73 (m, 2H), 3.37-3.45 (m, 1H), 3.61 (s, 2H), 4.00 (q, 2H, J=7.0), 5.89 (d, 1H, J=7.5), 6.81 (d, 1H, J=9.3), 6.89 (d, 2H, J=8.4), 7.26 (d, 2H, J=8.3), 7.92 (dd, 1H, J=9.3, 2.3), 8.10 (d, 1H, J=2.3), 9.47 (br s, 1H); MS (ESI): 413 (MH+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8](B1OC(C)(C)C(C)(C)O1)[CH:7]=[CH:6]2.[Cl:22][C:23]1[CH:24]=[C:25]([CH2:29][N:30]2[CH:34]=[CH:33][N:32]=[C:31]2[CH3:35])[N:26]=[N:27][CH:28]=1>>[ClH:22].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:23]1[CH:24]=[C:25]([CH2:29][N:30]3[CH:34]=[CH:33][N:32]=[C:31]3[CH3:35])[N:26]=[N:27][CH:28]=1)[CH:7]=[CH:6]2
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Reactant: COc1ccc2cc(B3OC(C)(C)C(C)(C)O3)ccc2c1
Product: COc1ccc2cc(-c3cnnc(Cn4ccnc4C)c3)ccc2c1
Product: Cl

Procedure:
The title compound, MS: m/e 331.4 (M+H+), was prepared from 2-(6-methoxy-naphthalen-2-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH:11]1([C:14](Cl)=[O:15])[CH2:13][CH2:12]1.[CH2:17](N(CC)CC)[CH3:18]>>[CH:11]1([C:14]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[O:15])[CH2:13][CH2:12][CH2:18][CH2:17]1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)C1CC1
Reactant: CCN(CC)CC
Product: O=C(O)c1ccc(NC(=O)C2CCCC2)cc1

Procedure:
4-Cyclopentanecarbonylamino-benzoic acid was prepared as described in Example 1B from 31.5 g (0.23 mol) of p-aminobenzoic acid and 17.3 g (0.23 mol) of cyclopropanecarboxylic acid chloride in the presence of triethylamine.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:21]([CH3:23])[CH3:22])[C:6]2[O:10][C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:20]=1)#[N:2].[NH2:24][CH2:25][C@H:26]1[CH2:31][CH2:30][C@H:29]([CH2:32][CH2:33][OH:34])[CH2:28][CH2:27]1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:21]([CH3:23])[CH3:22])[C:6]2[O:10][C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([NH:24][CH2:25][C@H:26]4[CH2:31][CH2:30][C@H:29]([CH2:32][CH2:33][OH:34])[CH2:28][CH2:27]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:20]=1)#[N:2]
Reactant: NC[C@H]1CC[C@H](CCO)CC1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)O)cc3)oc12
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@H]4CC[C@H](CCO)CC4)cc3)oc12

Procedure:
The title compound was prepared from 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoic acid (INTERMEDIATE 2), and 2-[trans-4-(aminomethyl)cyclohexyl]ethanol (INTERMEDIATE 8) as described in EXAMPLE 1. Mass spectrum (ESI) 446.1 (M+1).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C@H:18]([N:31]2[C:35](=[O:36])[CH:34]([C:37]3[CH:46]=[CH:45][C:40]4[O:41][CH2:42][CH2:43][O:44][C:39]=4[CH:38]=3)[NH:33][C:32]2=[O:47])[C:19](=[O:30])[NH:20][C:21]2[S:22][CH:23]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[N:25]=2)=[CH:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:29][O:28][C:26]([C:24]1[N:25]=[C:21]([NH:20][C:19](=[O:30])[C@@H:18]([N:31]2[C:35](=[O:36])[CH:34]([C:37]3[CH:46]=[CH:45][C:40]4[O:41][CH2:42][CH2:43][O:44][C:39]=4[CH:38]=3)[NH:33][C:32]2=[O:47])[CH2:17][C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:8][CH:9]=2)[S:22][CH:23]=1)=[O:27]
Reactant: COC(=O)c1csc(NC(=O)[C@H](Cc2cn(C(=O)OC(C)(C)C)c3ccccc23)N2C(=O)NC(c3ccc4c(c3)OCCO4)C2=O)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1csc(NC(=O)[C@H](Cc2c[nH]c3ccccc23)N2C(=O)NC(c3ccc4c(c3)OCCO4)C2=O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
To a cold solution of 3-[(S)-2-[4-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-2,5-dioxo-imidazolidin-1-yl]-2-(4-methoxycarbonyl-thiazol-2-ylcarbamoyl)-ethyl]-indole-1-carboxylic acid tert-butyl ester (78 mg, 0.118 mmol) in dichloromethane (10 mL), was added trifluoroacetic acid (2 mL, 26.0 mmol). The reaction mixture was stirred at room temperature for 1 hour. The volatiles were removed in vacuo and the residue was dissolved in ethyl acetate (100 mL), washed once with cold saturated aqeous sodium bicarbonate, water, brine and dried over sodium sulfate. The solvent was removed and the residue was purified by chromatographed over silica gel gradient eluted between 50% and 75% ethyl acetate in hexanes to afford 2-[(S)-2-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2,5-dioxo-imidazolidin-1-yl]-3-(1H-indol-3-yl)-propionylamino]-thiazole-4-carboxylic acid methyl ester (37 mg, 55%).
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24]([NH:26]C(=O)C2C=CC=CC=2)=[S:25])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH2:16][C:17]#[CH:18])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O1CCCC1.O>[CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24]([NH2:26])=[S:25])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH2:16][C:17]#[CH:18])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: C#CCc1c(C)nc2c(NCc3c(C)cccc3NC(=S)NC(=O)c3ccccc3)cccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C#CCc1c(C)nc2c(NCc3c(C)cccc3NC(N)=S)cccn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
To a solution of 8-[2-methyl-6-(3-benzoylthioureido)benzylamino]-3-(2propynyl)-2-methylimidazo[1,2-a]pyridine (0.59 g) in methanol (5.9 ml) and tetrahydrofuran (5.9 ml) was added a solution of potassium carbonate (0.174 g) in water (5 ml) and the mixture was stirred for 2 hours at room temperature. The solvent was removed under reduced pressure and the residue was dispersed into a mixture of water and chloroform. The chloroform layer was separated and washed with water and dried over magnesium sulfate. The residual oil was triturated with diethyl ether to give 8-(2-methyl-6-thioureidobenzylamino)-3-(2-propynyl)-2-methylimidazo[1,2-a]pyridine (0.36 g).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[NH2:2].[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]3([C:25]([NH:27][C:28]4[CH:29]=[N:30][C:31]([CH3:35])=[C:32](Br)[CH:33]=4)=[O:26])[CH2:24][CH2:23]3)=[CH:21][C:16]=2[O:15][CH2:14]1.O1C2C=CC(C3(C(NC4C=NC(C)=C(C5C=CC=CC=5)C=4)=O)CC3)=CC=2OC1>>[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]3([C:25]([NH:27][C:28]4[CH:33]=[C:32]([C:6]5[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=5)[C:1]([NH2:2])=[O:3])[C:31]([CH3:35])=[N:30][CH:29]=4)=[O:26])[CH2:24][CH2:23]3)=[CH:21][C:16]=2[O:15][CH2:14]1
Reactant: NC(=O)c1cccc(B(O)O)c1
Reactant: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1Br
Agent: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccccc1
Product: Cc1ncc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1cccc(C(N)=O)c1

Procedure:
3-(5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-methylpyridin-3-yl)benzamide was prepared from 3-carbamoylphenylboronic acid and 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-bromo-6-methylpyridin-3-yl)cyclopropanecarboxamide in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-5-phenylpyridin-3-yl)cyclopropanecarboxamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH2:13])[CH2:10][C@H:9]1[C:14](=[O:30])[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]2=[O:28])=[CH:18][C:17]=1[F:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:31][C:32]1[S:36][C:35]([C:37](O)=[O:38])=[CH:34][CH:33]=1.CN1CCOCC1>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C:37]([C:35]2[S:36][C:32]([Cl:31])=[CH:33][CH:34]=2)=[O:38])[CH2:10][C@H:9]1[C:14](=[O:30])[NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]2=[O:28])=[CH:18][C:17]=1[F:29])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)C[C@H]1C(=O)Nc1ccc(-n2ccccc2=O)cc1F
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C[C@@H](NC(=O)c2ccc(Cl)s2)C[C@H]1C(=O)Nc1ccc(-n2ccccc2=O)cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 37.9 %

Procedure:
(2S,4S)-4-Amino-2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (90 mg) was dissolved in acetonitrile (0.75 ml). A solution of 5-chlorothiophene-2-carboxylic acid (53 mg), NMM (33 mg) and IBCF (44 mg) in acetonitrile (0.75 ml), which was stirred for 30 min at 25° C., was added to the first solution. The complete mixture was stirred for 72 h at 25° C., evaporated to dryness and purified by chromatography (silica gel; gradient: n-heptane->AcOEt) to yield (2S,4S)-4-[(5-chloro-thiophene-2-carbonyl)-amino]2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (46 mg) as colorless solid. MH+=561.3 (Cl-isotopes)
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][CH2:13][C:14]3[O:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH2:13]([S:12][C:8]1[C:6]2[N:7]=[C:2]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:3]=[C:4]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:5]=2[N:11]=[CH:10][N:9]=1)[C:14]1[O:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S1CCN(c2nc(Cl)nc3c(SCc4ccco4)ncnc23)CC1
Reactant: C1CNCCN1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(SCc4ccco4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(furfuryl-thio)-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p: 173°-175° C.) and piperazine.
Reaction SMILES: [O:1]1[C:13]2[C:12]3[CH2:11][NH:10][CH2:9][CH2:8][C:7]=3[CH:6]=[CH:5][C:4]=2[O:3][CH2:2]1.[CH:14]([O:17][C:18]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:19]=1[C:20](O)=[O:21])([CH3:16])[CH3:15]>>[O:1]1[C:13]2[C:12]3[CH2:11][N:10]([C:20]([C:19]4[CH:23]=[C:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=[CH:26][C:18]=4[O:17][CH:14]([CH3:16])[CH3:15])=[O:21])[CH2:9][CH2:8][C:7]=3[CH:6]=[CH:5][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: c1cc2c(c3c1CCNC3)OCO2
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2ccc3c(c2C1)OCO3

Procedure:
Prepared in analogy to example 1.1 from 6,7,8,9-tetrahydro-[1,3]dioxolo [4,5-h]isoquinoline (CA [87091-23-4]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1). MS (m/e): 418.1 (M+H+).
Reaction SMILES: [H-].[Na+].O1C[CH2:6][CH2:5][CH2:4]1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=1.ICCC>CN(C)C=O>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][CH2:4][CH2:5][CH3:6])=[CH:11][CH:10]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCOCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
To a mixture of sodium hydride (66%, 360 mg, 15 mmol) and tetrahydrofuran (10 mL) was added 2-(4-bromophenyl)ethanol (1.5 g, 7.5 mmol) on an ice bath, the solution was stirred at room temperature for 1 hour. 1-Iodopropane (1.5 mL, 15 mmol) and N,N-dimethylformamide (10 mL) were added to the reaction solution on an ice bath, and the solution was stirred overnight at 45° C. The reaction solution was partitioned with water (100 mL) and heptane (200 mL). The organic layer was separated, and washed with brine. this solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (heptane:ethyl acetate=30:1), and the title compound (0.80 g, 3.3 mmol, 44%) was obtained as a colorless oil.