Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]#[N:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:15][CH2:16][CH2:17][NH3+:18].[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH:24]=O>>[Cl:2][C:3]1[C:4]([O:15][CH2:16][CH2:17][NH:18][CH2:24][C:20]2[O:19][CH:23]=[CH:22][CH:21]=2)=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]=[CH:10][C:9]([C:13]#[N:14])=[CH:8]2
Reactant: O=Cc1ccco1
Reactant: N#Cc1ccc2c(Cl)c(OCC[NH3+])ccc2c1
Agent: [Cl-]
Product: N#Cc1ccc2c(Cl)c(OCCNCc3ccco3)ccc2c1
Yield: 78 %

Procedure:
Prepared from 2-[(1-chloro-6-cyanonaphthalen-2-yl)oxy]ethanaminium chloride and furan-2-carbaldehyde in 78% yield as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[C:32](Cl)(=O)[O:33]C1C=CC([N+]([O-])=O)=CC=1.Cl.[O:46]1[CH2:50][CH2:49][C@H:48]([NH2:51])[CH2:47]1.C(N(C(C)C)C(C)C)C>ClCCl>[F:26][C:23]([F:24])([F:25])[C:22]([C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:12]2[CH2:11][CH2:10][CH:9]([S:8][C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:32]([NH:51][C@H:48]4[CH2:49][CH2:50][O:46][CH2:47]4)=[O:33])=[CH:3][CH:4]=3)[CH2:14][CH2:13]2)=[CH:17][CH:18]=1)([OH:31])[C:27]([F:30])([F:29])[F:28]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: N[C@H]1CCOC1
Reactant: Nc1ccc(SC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(SC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1)N[C@H]1CCOC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.7 %

Procedure:
2-(4-((4-(4-Aminophenylthio)piperidin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (1.076 mmol, 500 mg), and 4-nitrophenyl carbonochloridate (1.076 mmol, 217 mg) were combined in dichloromethane (10 mL) and the reaction mixture stirred at room temperature for 1 hour. (S)-Tetrahydrofuran-3-amine hydrochloride (2.153 mmol, 266 mg), and N-ethyl-N-isopropylpropan-2-amine (2.153 mmol, 0.356 mL, 278 mg) were added and the reaction mixture stirred for 30 minutes. The reaction mixture was washed with water, and the organic layer separated, dried, and concentrated under vacuum. The residue was purified by silica column chromatography (eluting with 0-10% methanol/dichloromethane gradient) to afford the title compound (284 mg). MS m/z 578.2 [M+H]+
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][C:16]([F:19])([F:18])[F:17])[C:5]=2[CH2:20][O:21][CH:22]2[CH2:28][CH:27]3[N:29]([C:30]4[S:31][C:32]5[CH:38]=[C:37]([C:39]([NH:41][CH2:42][C:43]([O:45]C)=[O:44])=[O:40])[CH:36]=[CH:35][C:33]=5[N:34]=4)[CH:24]([CH2:25][CH2:26]3)[CH2:23]2)[CH2:3][CH2:2]1.[Li+].[OH-]>O.O1CCOCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][C:16]([F:17])([F:18])[F:19])[C:5]=2[CH2:20][O:21][CH:22]2[CH2:28][CH:27]3[N:29]([C:30]4[S:31][C:32]5[CH:38]=[C:37]([C:39]([NH:41][CH2:42][C:43]([OH:45])=[O:44])=[O:40])[CH:36]=[CH:35][C:33]=5[N:34]=4)[CH:24]([CH2:25][CH2:26]3)[CH2:23]2)[CH2:3][CH2:2]1
Reactant: COC(=O)CNC(=O)c1ccc2nc(N3C4CCC3CC(OCc3c(-c5ccccc5OC(F)(F)F)noc3C3CC3)C4)sc2c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CNC(=O)c1ccc2nc(N3C4CCC3CC(OCc3c(-c5ccccc5OC(F)(F)F)noc3C3CC3)C4)sc2c1
Reaction time: 2 h

Procedure:
Methyl 2-(2-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6-carboxamido)acetate was subjected to a solution of 4N LiOH in water (2 mL) and dioxane (2 ml) and stirred for 2 hours. The solvent was reduced in vacuo and the mixture diluted with 5% citric acid (10 ml) and extracted with ethyl acetate (2×8 mL). The organics were combined and dried (MgSO4) then evaporated in vacuo. The product was purified with flash silica chromatography with methanol/dichloromethane with a 0-40% gradient to give the title compound as a white solid.
Reaction SMILES: C([O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[NH:21][C:22]([O:24][C@@H:25]2[CH:30]3[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]3)[CH2:26]2)=[O:23])[CH:15]=1)(=O)C1C=CC=CC=1.O.[OH-].[Li+]>CO.O>[N:27]12[CH2:28][CH2:29][CH:30]([CH2:31][CH2:32]1)[C@@H:25]([O:24][C:22](=[O:23])[NH:21][CH:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH2:12][CH2:11][CH2:10][OH:9])[CH:15]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:26]2
Reactant: O=C(NC(c1ccccc1)c1cccc(OCCCOC(=O)c2ccccc2)c1)O[C@H]1CN2CCC1CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(NC(c1ccccc1)c1cccc(OCCCO)c1)O[C@H]1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a stirred solution of 3-(3-(phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)-methyl)phenoxy)propyl benzoate (0.370 g, 0.72 mmol) in methanol (3.6 mL), was added a solution of lithium hydroxide monohydrate (0.060 g, 1.44 mmol) in water (1.2 mL). The reaction mixture was stirred at room temperature for 1 hour. Further lithium hydroxide monohydrate (0.060 g, 1.44 mmol) was added, and the reaction stirred at room temperature for a further 16 hours. The reaction mixture was heated at 40° C. for 3.5 hours and allowed to cool. The solvent was evaporate at reduced pressure, and the residue partitioned between ethyl acetate and water. The aqueous phase was further extracted with ethyl acetate (×2). The combined organic extracts were washed with 10% aqueous potassium carbonate (×2), saturated brine, and dried with anhydrous sodium sulfate. The mixture was filtered and the solvent evaporated at reduced pressure to afford the title compound (0.275 g, 93%).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]1[CH2:16][C:17]([N:19]([CH:28]([CH3:30])[CH3:29])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:18].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:41][Si:42]([CH3:50])([CH3:49])[O:43][CH2:44][CH2:45][O:46][CH2:47]Cl>CN(C=O)C>[O:1]=[C:2]1[C:8](=[CH:47][O:46][CH2:45][CH2:44][O:43][Si:42]([CH3:50])([CH3:49])[CH3:41])[C:7](=[O:9])[N:6]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]1[CH2:16][C:17]([N:19]([CH:28]([CH3:30])[CH3:29])[C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)=[O:18]
Reactant: C[Si](C)(C)OCCOCCl
Reactant: COc1ccc(N(C(=O)CN2C=CN(c3ccccc3)C(=O)CC2=O)C(C)C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C=CN(c3ccccc3)C(=O)C(=COCCO[Si](C)(C)C)C2=O)C(C)C)cc1
Reaction time: 0.17 h

Procedure:
A solution of 2-(2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-diazepin-1-yl)-N-isopropyl-N-(4-methoxyphenyl)acetamide (12p, 1.500 g) in anhydrous DMF (15 mL) under argon was cooled to 0-5° C. Sodium bis(trimethylsilyl)amide (0.6 M in toluene, 7.68 mL) was added via syringe followed 5 minutes later by chloromethyl 2-(trimethylsilyloxy)-1-ethyl ether (0.815 mL). After approximately 10 min., the reaction was quenched with glacial acetic acid and evaporated in vacuo. The residue was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was back-extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4, filtered and evaporated in vacuo. The crude product was purified on flash grade silica gel eluting with 2:5 ethyl acetate/hexane. Fractions containing the product were combined, evaporated in vacuo and dried under high vacuum to provide 2-[2,4-dioxo-5-phenyl-3-[2-(trimethylsilyloxy)-1-ethoxymethylene]-2,3,4,5-tetrahydro-1H-1,5-diazepin-1-yl]-N-isopropyl-N-(4-methoxyphenyl)acetamide(12q, 1.236 g) as a foam. 1H NMR (400 MHz, CDCl3) 0.00 (s, 9H), 0.95 (m, 2H), 1.04 (d, J=6 Hz, 3H), 1.06 (d, J=6 Hz, 3H), 3.62 (m, 3H), 3.83 (s, 3H), 3.91 (d, J=2 Hz, 2H), 4.02 (dd, J=5,10Hz, 1H), 4.15 (dd, J=8,10Hz, 1H), 4.95 (m, 1H), 5.93 (d, J=6 Hz, 1H), 5.99 (d, J=6 Hz, 1H), 6.94 (m, 2H), 7.11 (m, 2H), 7.33 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].S(Cl)([Cl:16])(=O)=O.C([O-])(O)=O.[Na+]>ClC1C=CC=CC=1.CC(N=NC(C#N)(C)C)(C#N)C>[Cl:16][CH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)c1c(C)cccc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Clc1ccccc1
Product: COC(=O)c1c(C)cccc1CCl
Reaction time: 2 h
Yield: 128.4 %

Procedure:
11.9 g of methyl 2,6-dimethylbenzoate are initially charged in 50 ml of chlorobenzene admixed at room temperature with 8.2 g of sulfuryl chloride and 40 mg of AIBN. The mixture is stirred at 60–90° C. for 2 h. Afterwards, the mixture is admixed with 80 ml of saturated NaHCO3 solution. After the phase separation, the organic phase is washed with 100 ml of 10% Na2SO3 solution, the organic phase is dried over magnesium sulfate and the chlorobenzene is distilled off in vacuo. 15.5 g of colorless liquid are obtained. The product is distilled under high vacuum (0.1 mbar, 66–77° C.). Yield: 10.2 g (71% of theory; 95.2 area %).
Reaction SMILES: [CH3:1][O:2][C:3](/[CH:5]=[CH:6]/[C:7]([OH:9])=[O:8])=[O:4].CCN=C=NCCCN(C)C.Cl.[CH2:22]([N:24]([CH2:30][CH3:31])[C:25](=[O:29])[C@@H:26](O)[CH3:27])[CH3:23]>ClCCl.CN(C1C=CN=CC=1)C>[C:7]([O:9][C@H:26]([C:25](=[O:29])[N:24]([CH2:30][CH3:31])[CH2:22][CH3:23])[CH3:27])(=[O:8])/[CH:6]=[CH:5]/[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)/C=C/C(=O)O
Reactant: CCN(CC)C(=O)[C@H](C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCN(CC)C(=O)[C@H](C)OC(=O)/C=C/C(=O)OC
Yield: 21.5 %

Procedure:
Following general procedure B2, (2E)-3-(methoxycarbonyl)prop-2-enoic acid (methyl hydrogen fumarate, MHF) (0.50 g, 3.84 mmol) was activated with N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDAC) (0.88 g, 4.60 mmol) in 12 mL of dichloromethane (DCM) at ca. 0° C. (2S)—N,N-Diethyl-2-hydroxypropanamide (0.44 g, 3.07 mmol) (0.44 g, 3.07 mmol) and 4-(N,N-dimethyl)aminopyridine (DMAP) (0.40 g, 3.18 mmol) were added to the activated carboxylic acid. After work-up and isolation, and purification by mass-guided preparative HPLC/lyophilization and by silica gel flash column chromatography (Biotage) using ethyl acetate (EtOAc) and hexanes afforded 0.17 g (18% yield) of the title compound (33) as a clear oil. 1H NMR (CDCl3, 400 MHz): δ 6.95-6.87 (m, 2H), 5.43 (q, J=6.8 Hz, 1H) 3.80 (s, 3H), 3.50-3.26 (m, 4H), 1.49 (d, J=6.4 Hz, 3H), 1.26 (t, J=6.8, 3H), 1.12 (t, J=7.6 Hz, 3H). MS (ESI): m/z 258.06 (M+H)+.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OOC1C=CC(C(C)C)=C(C(C)C)C=1O[O:27][C:28]([CH3:31])(C)C)(C)(C)C.[C]=O.[CH2:34]([OH:36])C>>[C:1]1([CH2:7][C:34]([O:27][CH2:28][CH3:31])=[O:36])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1
Reactant: CC(C)c1ccc(OOC(C)(C)C)c(OOC(C)(C)C)c1C(C)C
Reactant: CCO
Agent: [C]=O
Product: CCOC(=O)Cc1ccccc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 73.2 %

Procedure:
Toluene (1.38 g), ethanol (46 mg), bis(tert-butylperoxy)diisopropylbenzene (169 mg, 1 equivalent), and Pd(Xantphos)Cl2 (3.8 mg, 1 mol %) were added into a reaction kettle, into which 10 atm carbon monoxide was introduced. The reaction was heated to 120° C., and stirred at this constant temperature for 16 h. After the reaction was completed, carbon monoxide was discharged, and 60 mg ethyl phenylacetate was obtained by column chromatography, in a yield of 73%. The ethyl phenylacetate obtained was dissolved in 1,4-dioxane. 6 N sodium hydroxide solution was added, and the reaction was heated to 60° C. After 2 h of reaction, the pH value was adjusted to 1 by adding 2 N hydrochloric acid. After removing the organic solvent under reduced pressure, 46 mg product phenylacetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 92%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14](SC)[C:13]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)([C:17]([F:20])([F:19])[F:18])[O:12][N:11]=2)=[CH:6][C:5]=1[CH3:29].Cl[C:32]1C=C(C=CC=1)C(OO)=O.[S:42](S([O-])=O)([O-:45])(=O)=[O:43].[Na+].[Na+]>ClCCl>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]([S:42]([CH3:32])(=[O:45])=[O:43])[C:13]([C:21]3[CH:22]=[C:23]([Cl:28])[CH:24]=[C:25]([Cl:27])[CH:26]=3)([C:17]([F:20])([F:19])[F:18])[O:12][N:11]=2)=[CH:6][C:5]=1[CH3:29]
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2SC)cc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2S(C)(=O)=O)cc1C
Reaction time: 5 h

Procedure:
To a solution of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4-methylsulfanyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid methyl ester (428 mg) in dichloromethane (15 ml) was added 3-chloroperoxybenzoic acid (“MCPBA”) (500 mg) dropwise at ambient temperature. The reaction mixture was stirred for 5 hours then more 3-chloroperoxubenzoic acid (“MCPBA”) (300 mg) was added dropwise. The reaction mixture was allowed to stand at ambient temperature for 3 days. Then more 3-chloroperbenzoic acid (“MCPBA”) (100 mg) was added dropwise. The reaction mixture was allowed to stand at ambient temperature for another day. The reaction mixture was then treated with aqueous sodium metabisulfite (saturated) and extracted twice with dichloromethane. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (eluent: heptane/diethyl ether 6:4) to give 4-[5-(3,5-dichloro-phenyl)-4-methanesulfonyl-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid methyl ester (300 mg) as white foam. 1H-NMR (CDCl3, 400 MHz): 8.01-7.52 (m, 6H), 5.28 (s, 1H), 3.91 (s, 3H), 2.65 (s, 3H), 2.47 (s, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[N:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1[C:33](O)=[O:34]>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([NH:23][C:33]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][N:27]=4)=[O:34])[CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: O=C(O)c1cnccn1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)c5cnccn5)c4)CC3)cccc2n1
Yield: 89 %

Procedure:
The title compound was prepared in 89% yield according to the general procedure for the preparation of the amides (Method C) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 2-pyrazinecarboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].[CH2:11]([O:13][C:14](=[O:23])[C:15](=O)[CH2:16][C:17](=O)[CH:18]([CH3:20])[CH3:19])[CH3:12]>CCO.C1(C)C=CC=CC=1>[CH2:11]([O:13][C:14]([C:15]1[CH:16]=[C:17]([CH:18]([CH3:19])[CH3:20])[N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[N:10]=1)=[O:23])[CH3:12]
Reactant: CCOC(=O)C(=O)CC(=O)C(C)C
Reactant: COc1ccccc1NN
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(C(C)C)n(-c2ccccc2OC)n1
Temperature: 100 °C
Reaction time: 18 h
Yield: 65.2 %

Procedure:
2-Methoxyphenylhydrazine (14.07 g, 81 mmol) in EtOH (100 mL) was added dropwise to a refluxing solution of 5-methyl-2,4-dioxo-hexanoic acid ethyl ester (10 g, 53.7 mmol) in toluene (100 mL), under an argon atmosphere. The reaction mixture was stirred for 18 h at 100° C., allowed to cool to rt, concentrated, diluted with a saturated aqueous solution of sodium bicarbonate (250 mL), and extracted with EtOAc. The organic extracts were washed with a saturated aqueous solution of sodium bicarbonate, dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane/EtOAc, 95:5→7:3) to provide 10.1 g of the title compound. tR: 1.11 min (LC-MS 4);
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:18][C:19](=[O:28])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=2[OH:27])[CH2:16][C:15]2[C:17]3[C:11]([CH:12]=[CH:13][CH:14]=2)=[CH:10][CH:9]=[CH:8][C:7]=3[CH2:6]1)=[O:4].[C:29]([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:36][CH:37]=[CH2:38]>CN(C=O)C>[CH2:1]([O:2][C:3]([C:5]1([NH:18][C:19](=[O:28])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=2[O:27][CH2:36][CH:37]=[CH2:38])[CH2:6][C:7]2[C:17]3[C:11]([CH:10]=[CH:9][CH:8]=2)=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:16]1)=[O:4])[CH3:29]
Reactant: O=C([O-])[O-]
Reactant: C=CCBr
Reactant: COC(=O)C1(NC(=O)c2cccc(C)c2O)Cc2cccc3cccc(c23)C1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCOc1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2cccc3cccc(c23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
To a suspension of 2-(2-hydroxy-3-methyl-benzoylamino)-2,3-dihydro-1H-phenalene-2-carboxylic acid methyl ester (22) (175 mg, 0.47 mmol), anhydrous Cs2CO3 (306 mg, 0.94 mmol), and KI (15.6 mg, 0.09 mmol) in DMF (8 mL) is added 3-bromo-propene (199 μL, 2.35 mmol). The resulting reaction suspension is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (20 mL) and washed with water (1×5 mL) and brine (2×5 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5%-40% EtOAc in heptane) to give a pure product (23) as white solid (107 mg, 55%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:14][C:5]2[S:6][C:7]([C:9]([O:11]CC)=[O:10])=[CH:8][C:4]=2[CH2:3]1.C1COCC1.[OH-].[Li+].Cl>C(O)C.O>[CH3:1][C:2]1([CH3:15])[CH2:14][C:5]2[S:6][C:7]([C:9]([OH:11])=[O:10])=[CH:8][C:4]=2[CH2:3]1
Reactant: CCOC(=O)c1cc2c(s1)CC(C)(C)C2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC1(C)Cc2cc(C(=O)O)sc2C1
Temperature: 60 °C
Reaction time: 4 h
Yield: 91 %

Procedure:
In a 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser, 113b (4.00 g, 17.8 mmol) was dissolved in ethanol (50 mL). THF (50 mL), water (50 mL) and lithium hydroxide (854 mg, 35.6 mmol) were added, and the mixture was stirred at 60° C. for 4 h. After this time the reaction was cooled to room temperature and acidified with 2M hydrochloric acid to pH 1.5, and then extracted with ethyl acetate (2×200 mL). The organic layers were combined, washed with water (2×100 mL), followed by brine (100 ml) and dried over sodium sulfate. The drying agent was then separated by filtration. After evaporating the resulting filtrate, 113c was obtained in 91% yield (3.2 g) as a white solid: mp 170-172° C.; 1H NMR (300 MHz, CDCl3) δ 12.77 (s, 1H), 7.46 (s, 1H), 2.71 (s, 2H), 2.53 (s, 2H), 1.20 (s, 6H); MS (ESI−) m/z 195.0
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[N:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[C:24]1[S:25][CH:26]=[C:27]([CH2:29][C:30](O)=[O:31])[N:28]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:30](=[O:31])[CH2:29][C:27]2[N:28]=[C:24]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][N:18]=3)[S:25][CH:26]=2)[CH2:7]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C(O)Cc1csc(-c2cnccn2)n1
Product: O=C(Cc1csc(-c2cnccn2)n1)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 52.6 %

Procedure:
Example 37 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.056 g) and (2-pyrazin-2-yl-1,3-thiazol-4-yl)acetic acid (0.044 g) to give the title compound (0.05 g).
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][C:14]=1[CH3:21])=[O:12].[CH3:22][C:23]1[CH:24]=[C:25]([C:29]2[C:30]([C:35](O)=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:26]=[CH:27][CH:28]=1>>[CH3:22][C:23]1[CH:24]=[C:25]([C:29]2[C:30]([C:35]([N:3]3[CH2:4][C@H:5]4[C@H:1]([CH2:8][CH2:7][CH2:6]4)[C@H:2]3[CH2:9][NH:10][C:11]([C:13]3[N:20]4[C:16]([S:17][CH:18]=[CH:19]4)=[N:15][C:14]=3[CH3:21])=[O:12])=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CCC[C@@H]21
Reactant: Cc1cccc(-c2ccccc2C(=O)O)c1
Product: Cc1cccc(-c2ccccc2C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with commercially available 3′-methyl-biphenyl-2-carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH3:18][NH:19][CH3:20].[CH2:21]=O>CO>[CH3:18][N:19]([CH2:21][C:13]1[C:14]([O:16][CH3:17])=[CH:15][C:2]([OH:1])=[C:3]([CH:12]=1)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:20]
Reactant: COc1ccc(C(=O)c2ccccc2)c(O)c1
Reactant: CNC
Reactant: C=O
Solvent: CO
Product: COc1cc(O)c(C(=O)c2ccccc2)cc1CN(C)C
Yield: 99.9 %

Procedure:
228.3 g (1.0 mole) of 2-hydroxy-4-methoxy-benzophenone, 146.3 (1.3 moles, 40% aqueous solution) of dimethylamine, 105.4 g (1.3 moles, 37% aqueous solution) of formalin and 1200 ml of methanol was put into a flask, dissolved and heated under stirring at reflux temperature (68° to 70° C.) for 6 hours. When solvent was vacuum distilled off, 285 gr of 5-dimethylaminomethyl-2-hydroxy-4-methoxybenzophenone was obtained. The product had m.p. 69° C., infrared absorption at 1620 (Carbonyl), 2760 and 2800 (N--CH group) wave numbers, and neutralization equivalent (as nitrogen) 4.89% (Calculated 4.91%). The NMR spectrum provided evidence for the 5-position of the dimethylaminomethyl group.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH:7]=O)[CH2:3][CH2:2]1.[CH3:9][C:10]([CH:12]=[CH2:13])=[O:11].S(=O)(=O)(O)O.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:5]1[C:4]2([CH2:7][CH2:9][C:10](=[O:11])[CH:12]=[CH:13]2)[CH2:3][CH2:2][O:1][CH2:6]1
Reactant: C=CC(C)=O
Reactant: O=CC1CCOCC1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1C=CC2(CCOCC2)CC1
Reaction time: 3 h

Procedure:
5.00 g (43.8 mmol) tetrahydropyran-4-carboxaldehyde and 3.56 ml (43.9 mmol) methylvinylketone were boiled in 70 ml of toluene with 0.07 ml conc. sulphuric acid using a water separator. After 3 h another 3.56 ml methylvinylketone were added and the mixture was boiled for a further 3 h. After cooling the reaction mixture was taken up in ethyl acetate, washed with water, dried and concentrated by rotary evaporation.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][CH2:12][C:13](O)=O.C1CCC(N=C=NC2CCCCC2)CC1.[N:31]1[C:35]2[CH:36]=[CH:37][C:38]([C:40]([NH:42][NH2:43])=O)=[CH:39][C:34]=2[NH:33][CH:32]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:53])=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][CH2:12][C:13]1[S:53][C:40]([C:38]2[CH:37]=[CH:36][C:35]3[NH:31][CH:32]=[N:33][C:34]=3[CH:39]=2)=[N:42][N:43]=1
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Reactant: COc1ccc(OC)c(CCC(=O)O)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: COc1ccc(OC)c(CCc2nnc(-c3ccc4[nH]cnc4c3)s2)c1

Procedure:
The compound was synthesized starting from 3-(2,5-dimethoxyphenyl)propionic acid (210 mg; 1 mmol), DCC (206 mg; 1 mmol), benzimidazol-5-carbohydrazide (176 mg; 1 mmol) and Lawesson's reagent (606 mg; 1.5 mmol) as described in method 2; yield: 0.04 g (10.9%); MS m/z: 367.3 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 3.03 (t, 2H, 3J=7.5 Hz); 3.38 (t, 2H, 3J=7.5 Hz); 3.66 (s, 3H); 3.73 (s, 3H); 6.76 (dd, 1H, 4J=2.9 Hz, 3J=9.1 Hz); 6.82 (d, 1H, 4J=2.9 Hz); 6.89 (d, 1H, 3J=9.1 Hz); 7.81 (d, 1H, 3J=8.7 Hz); 7.89 (dd, 1H, 4J=1.7 Hz, 3J=8.7 Hz); 8.21 (d, 1H, 4J=1.7 Hz); 8.82 (s, 1H); HPLC (METHOD [A]): rt 12.62 min (93.1%)