Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]([OH:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Br[C:29]([F:36])([F:35])C(OCC)=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:25])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]([O:23][CH:29]([F:36])[F:35])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)C(F)(F)Br
Reactant: O=[N+]([O-])c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1OC(F)F
Temperature: 80 °C
Reaction time: 1 h

Procedure:
In a solution of 0.30 g of 5-(3,5-dichlorophenyl)-3-(3-hydroxy-4-nitrophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole in 20 mL of acetonitrile and 3 mL of water, 0.218 g of ethyl bromodifluoroacetate and 0.293 g of potassium carbonate were added, and stirred at 80° C. for 1 hour. After the completion of the reaction, the solvent was distilled off under reduced pressure, 10 mL of water was added in the residue, and extracted with ethyl acetate (20 mL×1). The organic phase was washed with water, and then dehydrated with and dried over saturated sodium chloride and then anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude aimed product as yellow resinous substance. The resulting product was used as such without purification for the next step.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1[C:13]2[C:8](=[C:9]([O:16][CH3:17])[C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[CH2:7][CH:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=1.[H][H]>C(O)C.[Pd]>[ClH:1].[NH2:2][CH2:3][C@H:4]1[C:13]2[C:8](=[C:9]([O:16][CH3:17])[C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[CH2:7][C@@H:6]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:5]1
Reactant: COc1ccc2c(c1OC)CC(c1ccccc1)C=C2CN
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1ccc2c(c1OC)C[C@@H](c1ccccc1)C[C@H]2CN
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To 0.2 g (0.67 mmol) of 1 aminomethyl 3,4-dihydro-5,6-dimethoxy-3-phenyl naphthalene hydrochloride, from Step 2, of Example 2, in 5 mL of absolute ethanol was added 0.05 g of 10% palladium supported on carbon. The reaction mixture was sealed under a blanket of hydrogen and stirred overnight at ambient temperature. The reaction mixture was flushed with nitrogen before it was filtered through Celite filter aid and washed with 15 mL of absolute ethanol and 15 mL of methylene chloride. The filtrate was concentrated to give 0.2 g (100% yield) of [1R,3S]1-aminomethyl-5,6-dimethoxy-3-phenyl 1,2,3,4-tetrahydro-naphthalene hydrochloride, m.p. 230°-231° C. 1H NMR (d6 -DMSO) delta 2.15-2.25 (m, 1H), 2.5-2.65 (m, 1H), 2.8-2.95 (m, 2H), 3.0-3.1 (m, 1H), 3.1-3.4 (m, 1H), 3.45-3.5 (m, 1 H), 3.66 (s, 3H), 3.78 (s, 3H), 6.95 (d, 1H), 7.12 (d, 1H), 7.2-7.3 (m, 1H), 7.35-7.45 (m, 4H), 8.0 (br s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([C:10]([F:15])([F:14])[CH2:11][CH2:12][CH3:13])(=[O:9])[O:6]CC.[ClH:16]>>[ClH:16].[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([C:10]([F:15])([F:14])[CH2:11][CH2:12][CH3:13])(=[O:6])[OH:9]
Reactant: CCCC(F)(F)P(=O)(CCCN)OCC
Agent: Cl
Product: CCCC(F)(F)P(=O)(O)CCCN
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 1.4 g (5.8 mMol) of ethyl 3-aminopropyl(1,1-difluorobutyl)phosphinate and 15 ml of 12M hydrochloric acid is stirred for 8 hours at 80° C. The reaction mixture is evaporated to dryness and the residue is recrystallized from ethanol/ether giving 3-aminopropyl-(1,1-difluorobutyl)phosphinic acid hydrochloride, m.p. 149°-151° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]([NH:15]C(=O)OC(C)(C)C)[C:9]2=[O:23])[CH:5]=[CH:6][CH:7]=1.Cl.O1CCOCC1>C(Cl)Cl>[ClH:1].[NH2:15][C@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14][N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:9]1=[O:23]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCN(c2cccc(Cl)c2)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N[C@H]1CCCCN(c2cccc(Cl)c2)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 196 %

Procedure:
To a stirred solution of (S)-tert-butyl 1-(3-chlorophenyl)-2-oxoazepan-3-ylcarbamate (35 mg, 0.10 mmol) in DCM (2 mL) was added 4.0 M HCl in dioxane (0.258 mL, 1.03 mmol) at rt under argon. The reaction was stirred at rt for 6 hr. The reaction mixture was concentrated and dried under vacuum to give (S)-3-amino-1-(3-chlorophenyl)azepan-2-one hydrochloride (27 mg, 0.098 mmol, 95% yield) as white solid. Anal. Calcd. for C12H15ClN2O m/z 238.2. found: 239.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:3]=1.[CH2:26]1[CH2:33][O:32][S:29](=[O:31])(=[O:30])[CH2:28][CH2:27]1.C(N(CC)CC)C>O1CCCC1>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:21][CH2:22][N:23]([S:29]([CH2:28][CH2:27][CH2:26][CH2:33][OH:32])(=[O:31])=[O:30])[CH2:24][CH2:25]2)[N:3]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: O=S1(=O)CCCCO1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCO)CC2)nc1N
Temperature: 150 °C
Yield: 85.9 %

Procedure:
The mixture of [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (100 mg, 0.290 mmol, Example 59), 1,4-butane sultone (81 uL, 0.870 mmol, Aldrich) and triethylamine (41 uL, 0.290 mmol) in tetrahydrofuran (3 mL) was heated at 150° C. for 1 hour using the Smith Creator microwave synthesizer. Upon cooling to room temperature, the reaction mixture was concentrated. Purification of the crude residue by reverse phase HPLC (C18, eluting with water and acetonitrile) gave [4-amino-2-[1-(4-hydroxy-butane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone as white solids (120 mg, 86%). HR-MS (ES, m/z) calculated for C21H29N5O5SF [(M+H)+] 482.Example 221, observed 482.1874.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][CH2:9][C:10](Cl)=[O:11].[CH:13]1[C:26]2[C:17](=[N:18][C:19]([CH2:27][NH2:28])=[C:20]3[C:25]=2[CH:24]=[CH:23][CH:22]=[CH:21]3)[CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[Cl:8][CH2:9][C:10]([NH:28][CH2:27][C:19]1[N:18]=[C:17]2[C:26](=[C:25]3[C:20]=1[CH:21]=[CH:22][CH:23]=[CH:24]3)[CH:13]=[CH:14][CH:15]=[CH:16]2)=[O:11]
Reactant: NCc1nc2ccccc2c2ccccc12
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)NCc1nc2ccccc2c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (460 μL, 3.30 mmol), followed by a solution of chloroacetyl chloride (175 μL, 2.20 mmol) in CH2Cl2 (5 mL) were added dropwise over 5 minutes to a solution of the amine 8 (229 mg, 1.10 mmol) dissolved in CH2Cl2 (15 mL) at 0° C. The reaction mixture was then allowed to warm to ambient temperature and stirred for 2 hours. The solvent was removed under reduced pressure and the reaction crude purified via flash chromatography over silica eluting with a gradient of CH2Cl2 to 1% MeOH/99% CH2Cl2. Evaporation of the solvents under reduced pressure yielded the chloro 9 as an off-white solid (177 mg, 56.5% over three steps).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:3]=1[C:4]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5]>[OH-].[NH4+].O>[NH2:15][C:12]1[CH:13]=[CH:14][C:2]([OH:1])=[C:3]([CH:11]=1)[C:4]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5]
Reactant: O=C(O)CCC(=O)c1cc([N+](=O)[O-])ccc1O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(O)c(C(=O)CCC(=O)O)c1
Reaction time: 1 h
Yield: 45.7 %

Procedure:
A solution of 3-(2-hydroxy-5-nitrobenzoyl)propionic acid (5.5 g, 0.023 mole) in ammonium hydroxide solution (5N; 100 ml) was added to a stirred, boiling solution of ferrous sulphate heptahydrate (45 g, 0.161 mole) in water (200 ml). Stirring under reflux was continued for a further 1 hour, ammonium hydroxide solution was added to pH 9, the mixture was filtered through Kieselguhr and evaporated to dryness. The solid residue was crystallised from ethanol to give pale yellow needles of 3-(5-amino-2-hydroxybenzoyl)propionic acid (2.2 g, 46% m.p. 158°-160°). (Found: M+, 209. C10H11NO4 requires: M, 209).
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[N:9]([CH3:10])[N:8]=[C:7]([C:11]2[CH:16]=[N:15][CH:14]=[CH:13][N:12]=2)[N:6]=1)C.[ClH:20]>O>[OH2:3].[ClH:20].[ClH:20].[CH3:10][N:9]1[C:5]([CH:4]=[O:3])=[N:6][C:7]([C:11]2[CH:16]=[N:15][CH:14]=[CH:13][N:12]=2)=[N:8]1
Reactant: CCOC(OCC)c1nc(-c2cnccn2)nn1C
Agent: Cl
Solvent: O
Product: Cn1nc(-c2cnccn2)nc1C=O
Temperature: 60 °C
Yield: 209.2 %

Procedure:
The acetal from step 2, 2-[5-(diethoxymethyl)-1-methyl-1H-1,2,4-triazol-3-yl]pyrazine (44.5 g, 0.17 mol) was dissolved in water (150 mL) and conc. HCl (30.0 mL of 12 M, 0.36 mol, ˜2 equiv). The solution was degassed with nitrogen for 2 min and heated in an oil bath at a bath temperature of 60° C for 2 h, resulting in complete hydrolysis of the acetal group. The volatiles were removed in vacuo, affording a yellow solid (49.8 g). This was suspended in dichloromethane (1 L), refluxed under nitrogen for 1 h, then filtered while still hot. The filter cake was washed with dichloromethane and dried in vacuo at 50° C. for 4 h, affording the title product (41.0 g, 81%) as a hygroscopic yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 4.21 (s, 3H), 8.50 (br s, 4H), 8.75 (m, 2H), 9.27 (s, 1H), 10.01 (s, 1H). MS (APCI) calcd for C8H7N5O: 189.07, found (M+H+): 190.1, 208.1 (hydrate); Anal. Calcd. For C8H11Cl2N5O2: C, 34.30; H, 3.96; N, 25.00; O, 11.42; Cl, 25.31. Found: C, 33.43; H, 3.98; N, 24.70; O, 11.17; Cl, 25.44.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].[CH3:15]O>>[CH3:15][O:9][C:8](=[O:10])[CH2:7][CH2:6][CH2:5][O:4][C:3]1[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=1[Br:1]
Reactant: CO
Reactant: O=C(O)CCCOc1ccccc1Br
Product: COC(=O)CCCOc1ccccc1Br
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 1.4 g of 4-(2-bromophenoxy)-butyric acid in 22 ml of methanol is mixed with 1 g of Amberlyst 15 and stirred for 5 hours at room temperature. Then, it is filtered from the Amberlyst 15, the filtrate concentrated by evaporation, the residue is taken up in diethyl ether, washed with dilute sodium carbonate solution, dried (Na2SO4) and concentrated by evaporation. 1.5 g of 4-(2-bromophenoxy)-butyric acid methyl ester is obtained as a colorless oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[CH:3]([NH:8][C:9]([C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)=[O:24])=[CH:18][CH:17]=2)=[CH:14][N:15]=1)=[O:10])[C:4]([O:6]C)=[O:5].O.[OH-].[Li+].Cl>C1COCC1>[CH3:1][CH:2]([CH3:36])[CH:3]([NH:8][C:9]([C:11]1[O:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:33])[F:35])[CH:27]=3)=[O:24])=[CH:20][CH:21]=2)=[CH:14][N:15]=1)=[O:10])[C:4]([OH:6])=[O:5]
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)o1)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(NC(=O)c1ncc(-c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)o1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 3-methyl-2-(5-(4-(3-(3-(trifluoromethyl)phenyl)ureido)phenyl) oxazole-2-carboxamido)butanoate (Example 1, 150 mg) in THF (3 ml) was added 1 M aqueous solution of Lithium hydroxide monohydrate (0.6 ml) and the mixture was stirred for 4 hours at RT. The reaction mixture was acidified with dilute HCl and extracted with EtOAc. The organic layer was separated, dried over Na2SO4, concentrated under reduced pressure and then crystallized in EtOAc to give the title compound. Yield: 125 mg (85%); 1H NMR (DMSO-d6, 300 MHz): δ 12.93 (bs, 1H), 9.14 (s, 1H), 9.06 (s, 1H), 8.64 (d, 1H), 8.03 (d, 1H), 7.81 (s, 1H), 7.8 (d, 2H), 7.64 (d, 2H), 7.58 (dd, 1H), 7.52 (dd, 1H), 7.34 (m, 1H), 4.28, (m, 1H), 2.26 (m, 1H), 0.95 (d, 6H); MS (ES+) m/z 491 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[Cl:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([Cl:17])[C:15]=1[OH:16])[C:9](OC)=[O:10].Cl>>[Cl:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([Cl:17])[C:15]=1[OH:16])[C:9]([NH:1][CH2:2][CH2:3][OH:4])=[O:10]
Reactant: NCCO
Reactant: COC(=O)c1cc(Cl)c(O)c(Cl)c1
Agent: Cl
Product: O=C(NCCO)c1cc(Cl)c(O)c(Cl)c1
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
A 2 L, 3 necked, round bottom flask was charged with 2-aminoethanol (240 gm; 3.93 moles) and heated to 80° C. Methyl 3,5-dichloro-4-hydroxybenzoate (432 gm; 1.96 moles ) was added in portions through a powder funnel. The resulting amber solution was heated to 145° C. and the liberated methanol distilled into a Dean Stark trap. The reaction requires about 3.5 hrs. Upon completion, the solution was cooled to 90°-100° C. and dissolved in 1.95 L H2O. The aqueous solution was cooled to 25° C., placed in an ice bath and made slightly acidic with concentrated hydrochloric acid (196 ml; 2.35 moles). The product precipitated and filtration afforded a white solid. After drying at 50° C. in a vacuum oven, the product darkened slightly. The crude material (384.4 gm; 78.8%) was ground and passed through a No. 20 mesh screen to produce 3,5-dichloro-4-hydroxy-N-(2-hydroxyethyl)benzamide as a cream colored solid (m.p. 174°-178° C.) which is suitable for use in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][N:7]=1.C(N(CCCC)CCCC)CCC.[I-].ClC1C=CC=C[N+]=1C.[NH2:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH:39]([NH:42][C:43]2[N:47]([CH2:48][C:49]3[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=3)[C:46]3[CH:56]=[CH:57][CH:58]=[CH:59][C:45]=3[N:44]=2)[CH2:38][CH2:37]1>ClCCl>[NH2:1][C:2]1[C:3]([C:8]([NH:33][CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][CH:39]([NH:42][C:43]3[N:47]([CH2:48][C:49]4[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=4)[C:46]4[CH:56]=[CH:57][CH:58]=[CH:59][C:45]=4[N:44]=3)[CH2:38][CH2:37]2)=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccnc1C(=O)O
Reactant: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCCCN(CCCC)CCCC
Product: Nc1nccnc1C(=O)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38 %

Procedure:
To a stirred mixture of 2.1 parts of 3-amino-2-pyrazinecarboxylic acid, 2.8 parts of N,N-dibutylbutanamine and 195 parts of dichloromethane were added 3.83 parts of 2-chloro-1-methlypridinium iodide. After stirring for 15 minutes at room temperature, 5.5 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine were added and stirring was continued for one hour. The reaction mixture was washed with water, dried, filtered and evaporated. The residue was stirred in 2,2'-oxybispropane. The latter was decanted and the residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 1,1'-oxybisethane, yielding 2.8 parts (38%) of 3-amino-N-[2-[4-[[1-[(4-fluorophenyl)-methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-2-pyrazinecarboxamide; mp. 156.9° C. (compound 113).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[S:10][CH:11]=[C:12](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)[N:13]=1.C(Cl)(=O)C([Cl:22])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[S:10][CH:11]=[C:12](/[CH:14]=[CH:15]/[C:16]([Cl:22])=[O:18])[N:13]=1
Reactant: O=C(O)/C=C/c1csc(-c2c(Cl)cccc2Cl)n1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)/C=C/c1csc(-c2c(Cl)cccc2Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a suspension of (E)-3-(2-(2,6-dichlorophenyl)thiazol-4-yl)acrylic acid (5.7 g, 19 mmol) in DCM (20 mL) was added oxalyl chloride (4.8 g, 38 mmol) and 2 drops of DMF. The resulting mixture was stirred for 2 hours at room temperature and then concentrated under reduced pressure to give the crude desired product (6.0 g, 99% yield), which was used in the next step without purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][NH2:14])=[CH:7][N:6]=1.C1(C)C=CC=CC=1>O>[N:6]1[C:7]2[NH:14][CH2:13][CH2:12][CH2:11][C:8]=2[CH:9]=[CH:10][C:5]=1[CH2:4][CH2:3][CH2:2][NH2:1]
Reactant: NCCCc1ccc(CCCN)nc1
Solvent: O
Solvent: Cc1ccccc1
Product: NCCCc1ccc2c(n1)NCCC2
Reaction time: 15 h
Yield: 94.6 %

Procedure:
A 100 mL round-bottom flask equipped with a N2 inlet was charged with 1-3 (2.54 g, 13.1 mmol), toluene (65 mL), and freshly grounded NaNH2 (2.69 g, 65.5 mmol). The flask was evacuated and back filled with N2 and placed in a 90° C. oil bath. After 15 h, water (1.18 mL, 65.5 mmol) was added slowly without removing the flask from the oil bath. Caution: an exothermic reaction occurs upon addition of water. After the addition of water, the resulting mixture was filtered while hot, followed by 65 mL of hot toluene (90° C.). The mother liquor was concentrated to yield 2.37 g (94%) of 1-4.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[CH2:23]([O:33][C:34]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[CH2:23]([O:33][C:34]1[CH:41]=[CH:40][C:37]([C:38]2[N:2]([CH3:1])[N:3]=[C:4]([C:5]3[C:6]([Cl:12])=[CH:7][CH:8]=[CH:9][C:10]=3[Cl:11])[N:39]=2)=[CH:36][CH:35]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CN(N=C(Cl)c1c(Cl)cccc1Cl)S(=O)(=O)c1ccccc1
Reactant: CCCCCCCCCCOc1ccc(C#N)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: CCCCCCCCCCOc1ccc(-c2nc(-c3c(Cl)cccc3Cl)nn2C)cc1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 32.2 %

Procedure:
A mixture of 1.10 g of N-methyl-N-phenylsulfonyl-2,6-dichlorobenzohydrazonoyl chloride, 0.70 g of 4-decyloxybenzonitrile, 0.4 g of anhydrous aluminium chloride and 3 ml of o-dichlorobenzene was stirred in an oil bath at a temperature of 140° C. for 30 minutes. After the cooling, the resulting solution was dissolved in 100 ml of chloroform, washed with diluted hydrochloric acid solution, diluted sodium hydroxide solution and saline water in this order, dried over anhydrous magnesium sulfate and concentrated under a reduced pressure. The resulting concentrate was purified through a chromatography of silica gel column using a mixed solution of hexane and ethyl acetate as a developing solvent to obtain 0.40 g of the given compound (melting point: 60.0°-64.0° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:22][C:21]([SH:23])=[N:20][N:19]=4)[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)=[CH:5][CH:4]=1.Br[CH2:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[C:29]#[N:30]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:22][C:21]([S:23][CH2:25][C:26]5[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=5)[C:29]#[N:30])=[N:20][N:19]=4)[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)=[CH:5][CH:4]=1
Reactant: N#Cc1cccc(CBr)c1
Reactant: COc1ccc(-n2cnc3ccc(-c4nnc(S)o4)cc32)cc1
Product: COc1ccc(-n2cnc3ccc(-c4nnc(SCc5cccc(C#N)c5)o4)cc32)cc1
Yield: 24 %

Procedure:
In the same manner as in Example 1 and using 5-[1-(4-methoxyphenyl)-1H-benzimidazol-6-yl]-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 3-(bromomethyl)benzonitrile instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 24%) was obtained as colorless crystals.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:33]=3[NH:32][CH:31]=[C:30]4[CH2:34][CH2:35][C:36]([O:38]C(C)(C)C)=[O:37])[N:21]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18])#[N:9]>ClCCl>[C:8]([C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:33]=3[NH:32][CH:31]=[C:30]4[CH2:34][CH2:35][C:36]([OH:38])=[O:37])[N:21]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18])#[N:9]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)OC(C)(C)C)c[nH]c34)no2)cc1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)O)c[nH]c34)no2)cc1C#N
Reaction time: 2 h
Yield: 68.1 %

Procedure:
Trifluoroacetic acid (0.37 mL) was added to a solution of 1,1-dimethylethyl 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D9) (45 mg) in dichloromethane (0.5 mL) at RT. The resulting solution was stirred for 2 hours. The reaction mixture was concentrated. The residue was recrystallized from dichloromethane to afford 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E3) (27 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.40 (6H, d), 2.67 (2H, t), 3.03 (2H, t), 5.01 (1H, m), 7.22 (1H, t), 7.28 (1H, d), 7.46 (1H, d), 7.83 (1H, d), 7.95 (1H, dd), 8.21 (1H, dd), 8.39 (1H, d), 10.86 (1H, s), 12.12 (1H, br s). MS (ES): C23H20N4O4 requires 416; found 417.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].Cl[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1[C:22]#[N:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:22]([C:13]1[CH:14]=[C:15]([C:18]([F:19])([F:20])[F:21])[CH:16]=[CH:17][C:12]=1[O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])#[N:23]
Reactant: O=C(O)c1cccc(O)c1
Reactant: N#Cc1cc(C(F)(F)F)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(C(F)(F)F)ccc1Oc1cccc(C(=O)O)c1
Reaction time: 65 h
Yield: 39.1 %

Procedure:
3-Hydroxybenzoic acid (27.6 g), 4-chloro-3-cyano-benzotrifluoride (41.1 g) and anhydrous potassium carbonate (55.2 g) were stirred together for 71/2 hours at 100° C. in dry dimethylformamide (500 ml) and then left at room temperature for 65 hours. The solvent was then removed under reduced pressure and the residue taken up in water and acidified with dilute hydrochloric acid. The solid which separated was washed with water, dissolved in ether and the solution dried and concentrated. The colourless solid which separated was recrystallised to give the benzoic acid derivative (24.0 g) with a melting point of 224°-226° C.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][CH:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:22]([OH:25])[CH2:23][N:24]=2)=[CH:15][CH:14]=1)[CH3:11]>ClCCCl>[CH2:10]([O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[O:20][CH:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:22]([O:25][C:8](=[O:9])[NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:23][N:24]=2)=[CH:17][CH:18]=1)[CH3:11]
Reactant: O=C=Nc1ccccc1
Reactant: CCOc1ccc(C2=NCC(O)C(c3ccccc3)O2)cc1
Solvent: ClCCCl
Product: CCOc1ccc(C2=NCC(OC(=O)Nc3ccccc3)C(c3ccccc3)O2)cc1
Temperature: 80 °C
Yield: 31.2 %

Procedure:
Phenyl isocyanate (0.38 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of (5RS, 6SR)-2-(4-ethoxyphenyl)-6-phenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (0.8 g) in 1,2-dichloroethane (10 cc). The solution obtained is heated to 80° C. for 3 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is purified by chromatography on silica (0.063-0.2 mm; 100 g), contained in a column 2 cm in diameter, collecting 20-cc fractions. Fractions 3 and 4, eluted with a mixture of cyclohexane and ethyl acetate (6:4 by volume), are concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The solid obtained is then purified again by chromatography on silica (0.063-0.2 mm; 100 g), contained in a column 2 cm in diameter, collecting 20-cc fractions. Fractions 5 to 10, eluted with a mixture of cyclohexane, ethyl acetate and triethylamine (65:30:5 by volume), are concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in ethyl acetate, (5RS, 6SR)-2-(4-ethoxyphenyl)-6-phenyl-5-phenylcarbamoyloxy-5,6-dihydro-4H-1,3-oxazine (0.35 g), m.p. 80° C., is obtained.