Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[CH3:32][N:33]1[CH:37]=[N:36][N:35]=[C:34]1[CH:38]([NH2:40])[CH3:39].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:40][CH:38]([C:34]1[N:33]([CH3:32])[CH:37]=[N:36][N:35]=1)[CH3:39])=[O:4]
Reactant: CC(N)c1nncn1C
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(NC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1)c1nncn1C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 17 mg, 0.039 mmol), (R/S)-1-(4-methyl-4H-1,2,4-triazol-3-yl)ethanamine (7.46 mg, 0.059 mmol), 4-methylmorpholine (15.95 mg, 0.158 mmol), and HATU (19.48 mg, 0.051 mmol) were dissolved in DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=12.2 min) to provide 2-hydroxy-N-(1-(4-methyl-4H-1,2,4-triazol-3-yl)ethyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (8 mg, 0.014 mmol, 34.6% yield) as a racemic mixture of diastereomers. LCMS=540.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.90 (1 H, s), 8.16 (2 H, d, J=8.36 Hz), 7.52-7.77 (7 H, m), 5.36 (1 H, q), 5.21 (1 H, s), 3.62 (3 H, s), 1.69 (3 H, d, J=7.04 Hz); HPLC peak RT=8.4 min (Method A).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].[S:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]=[C:11]1[C:19]1[O:23][C:22](=[O:24])[C:21]2([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[N:20]=1>CN1CCOCC1>[S:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]=[C:11]1[C:19]([NH:20][C:21]1([C:22]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6])=[O:24])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23]
Reactant: O=C1OC(c2cc3ccccc3s2)=NC12CCCCC2
Reactant: CSCC[C@H](N)C(=O)O
Solvent: CN1CCOCC1
Product: CSCC[C@H](NC(=O)C1(NC(=O)c2cc3ccccc3s2)CCCCC1)C(=O)O
Yield: 22.4 %

Procedure:
10 ml of N-methylmorpholine was added to 522 mg (3.5 mmol) of L-methionine and 500 mg (1.75 mmol) of 2-(2-benzothienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one, and the mixture was stirred and refluxed under heating overnight. The reaction solution was distilled off under reduced pressure, a 10% aqueous potassium hydrogensulfate solution was added thereto, and the mixture was extracted with methylene chloride three times. The obtained organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue, and the mixture was stirred overnight. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 170 mg (22%) of the title compound.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[CH3:13][O:14][C:15]1[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=1[CH:17]=[N+:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[CH3:13][O:14][C:15]1[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=1[CH:17]([C:8]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:11]=[CH:10][CH:9]=1)[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: c1ccc(-n2cccc2)cc1
Reactant: COc1ccccc1C=[N+]1CCOCC1
Agent: [Cl-]
Product: COc1ccccc1C(c1cccn1-c1ccccc1)N1CCOCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-phenyl-1H-pyrrole and 4-(2-methoxy-benzylidene)-morpholin-4-ium chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[Br:10][C:11]1[CH:12]=[CH:13][C:14]([Cl:20])=[C:15]([CH:19]=1)[C:16](O)=O>>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([Cl:20])=[C:15]([C:16]2[NH:9][C:4]3[C:5]([N:8]=2)=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)[CH:19]=1
Reactant: Cc1cnc(N)c(N)c1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Product: Cc1cnc2nc(-c3cc(Br)ccc3Cl)[nH]c2c1

Procedure:
Intermediate I-4 was synthesized in a similar fashion as described in the synthesis of I-2a using 5-methylpyridine-2,3-diamine and 5-bromo-2-chlorobenzoic acid. 1H NMR (400 MHz, DMSO) δ 8.18 (d, J=2.4 Hz, 1H), 8.07 (s, 1H), 7.68 (s, 1H), 7.60 (dd, J=2.2, 8.4 Hz, 1H), 7.51 (d, J=8.5 Hz, 1H), 2.39 (s, 3H). MS M/Z=322/324 (M+1).
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=O)[C:9]([CH3:12])([CH3:11])[CH3:10].[Li]CCCC.[NH4+].[Cl-]>C1COCC1>[C:9]([C:8]1[NH:7][C:2]2[C:1]([CH:14]=1)=[CH:6][CH:5]=[CH:4][CH:3]=2)([CH3:12])([CH3:11])[CH3:10]
Reactant: Cc1ccccc1NC(=O)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc2ccccc2[nH]1
Temperature: 15 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
To a solution of N-o-tolylpivalamide (30.0 g, 159 mmol) in dry THF (100 mL) was added dropwise n-BuLi (2.5 M in hexane, 190 mL) at 15° C. After addition, the mixture was stirred overnight at 15° C. The mixture was cooled in an ice-water bath and treated with saturated NH4Cl. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was purified by column chromatography on silica gel to give 2-tert-butyl-1H-indole (24 g, 88%). 1H NMR (300 MHz, CDCl3) δ 7.99 (br. s, 1 H), 7.54 (d, J=7.2 Hz, 1 H), 7.05 (d, J=7.8 Hz, 1 H), 7.06-7.13 (m, 2 H), 6.26 (s, 1 H), 1.39 (s, 9 H).
Reaction SMILES: C([O:8][C:9]1[CH:24]=[CH:23][C:22]([C:25]2[O:26][C:27]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)=[CH:28][CH:29]=2)=[CH:21][C:10]=1[C:11]([O:13]CC1C=CC=CC=1)=[O:12])C1C=CC=CC=1.O1CCCC1>[Pd].CO>[F:38][C:36]([F:37])([F:39])[C:33]1[CH:32]=[CH:31][C:30]([C:27]2[O:26][C:25]([C:22]3[CH:21]=[C:10]([C:11]([OH:13])=[O:12])[C:9]([OH:8])=[CH:24][CH:23]=3)=[CH:29][CH:28]=2)=[CH:35][CH:34]=1
Reactant: O=C(OCc1ccccc1)c1cc(-c2ccc(-c3ccc(C(F)(F)F)cc3)o2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc(-c2ccc(-c3ccc(C(F)(F)F)cc3)o2)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
A mixture of benzyl 2-benzyloxy-5-[5-(4-trifluromethylphenyl)-2-furyl]benzoate (2.64 g), 5% palladium on carbon (2.6 g), tetrahydrofuran (50 ml) and methanol (50 ml) was stirred under a hydrogen atmosphere at normal pressure and room temperature for 30 min. Palladium on carbon was removed by filtration, and the filtrate was concentrated. The residue was recrystallized from ethanol to give 5-[5-(4-trifluoromethylphenyl)-2-furyl]salicylic acid (1.07 g, yield 62%) as a colorless crystalline powder. melting point: 272–273° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:25])[C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])=[N:18][C:13]3=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[N:26]([C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=1)=[C:27]=[O:28]>CN(C)C=O.C(OCC)(=O)C>[F:8][C:7]1[CH:6]=[CH:5][C:4]([N:9]([CH3:25])[C:10]2[N:15]=[C:14]3[S:16][C:17]([NH:19][C:20]([CH:22]4[CH2:23][CH2:24]4)=[O:21])=[N:18][C:13]3=[CH:12][CH:11]=2)=[CH:3][C:2]=1[NH:1][C:27](=[O:28])[NH:26][C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:36])([F:38])[F:37])=[CH:31][CH:30]=1
Reactant: CN(c1ccc(F)c(N)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(c1ccc(F)c(NC(=O)Nc2ccc(C(F)(F)F)cc2)c1)c1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.3 %

Procedure:
N-{5-[(3-Amino-4-fluorophenyl)(methyl)amino][1,3]thiazolo[5,4-b]pyridin-2-yl}cyclopropanecarboxamide (120 mg, 0.33 mmol) was dissolved in N,N-dimethylformamide (2.0 mL), 1-isocyanato-4-(trifluoromethyl)benzene (58 μL, 0.40 mmol) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (10 mL), and washed successively with saturated aqueous sodium hydrogen carbonate solution (10 ml) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=30/70→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (130 mg, 71%) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([S:7]([NH:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])(=[O:9])=[O:8])[N:3]=1.[C:19](OCC)(OCC)([O:21][CH2:22][CH3:23])[CH3:20]>C(#N)C.C(O)(=O)C>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[NH:10][S:7]([C:4]1[N:3]=[C:2]([N:1]=[C:19]([O:21][CH2:22][CH3:23])[CH3:20])[NH:6][N:5]=1)(=[O:9])=[O:8]
Reactant: CCOC(C)(OCC)OCC
Reactant: Nc1nc(S(=O)(=O)Nc2c(Cl)cccc2Cl)n[nH]1
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOC(C)=Nc1nc(S(=O)(=O)Nc2c(Cl)cccc2Cl)n[nH]1

Procedure:
6.16 g (20.0 mmol) 5-amino-N-(2,6-dichlorophenyl)-1H-1,2,4-triazole-3-sulphonamide was heated in 50 ml acetonitrile with 4.2 ml (23.0 mmol) triethyl orthoacetate and 3 drops glacial acetic acid for 5 hours under reflux. The mixture was cooled and evaporated to dryness. The residue was recrystallized from ethyl acetate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:3]=1.[NH2:19][C:20]1[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][OH:26])=[CH:22][CH:21]=1>CN1C(=O)CCC1>[Cl:18][C:14]1[CH:13]=[C:12]([C:4]2[N:3]=[C:2]([NH:19][C:20]3[CH:28]=[CH:27][C:23]([CH2:24][CH2:25][OH:26])=[CH:22][CH:21]=3)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccc(Cl)c2)n1
Solvent: CN1CCCC1=O
Product: OCCc1ccc(Nc2cc(C(F)(F)F)nc(-c3cccc(Cl)c3)n2)cc1
Yield: 32.9 %

Procedure:
Following General Procedure A2, 4-chloro-2-(3-chlorophenyl)-6-(trifluoromethyl)pyrimidine (0.100 g, 0.34 mmol) in NMP (3 mL) was reacted with 4-aminophenethyl alcohol (0.094 g, 0.68 mmol) to afford the title compound (0.044 g, 44%) as an off-white solid. MW=393.79. 1H NMR (DMSO-d6, 500 MHz) δ 10.20 (s, 1H), 8.30-8.25 (m, 2H), 7.78-7.56 (m, 4H), 7.29 (d, J=8.5 Hz, 2H), 7.07 (s, 1H), 4.64 (t, J=5.2 Hz, 1H), 3.66-3.60 (m, 2H), 2.74 (t, J=7.0 Hz, 2H); APCI MS m/z 394 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:20])([F:19])[C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1.[N+:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])#[C-:22]>C1COCC1>[F:8][C:9]([F:20])([F:19])[C:10]1[CH:18]=[CH:17][C:13]([C:14]2[O:15][CH:22]=[N:21][C:23]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: [C-]#[N+]CC(=O)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ncoc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 62.8 %

Procedure:
Triethylamine (10.0 mL, 71.9 mmol) was added to a solution of 4-(trifluoromethyl)benzoyl chloride (5.0 g, 24.0 mmol) in THF (50 mL) at 0° C. Ethyl 2-isocyanoacetate (2.9 mL, 26.4 mmol) was added dropwise and the mixture was warmed to ambient temperature. After 3.5 days the reaction mixture was partitioned between EtOAc (100 mL) and H2O (100 mL). The separated aqueous phase was extracted with EtOAc, and the combined organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Chromatography on silica gel (Analogix® Intelliflash 280™; SF40-150 g column; 20% to 50% EtOAc/hexanes eluant, 30 min) yielded 4.30 g (63%) of the title compound as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.18 (d, J=8.2, 2H), 7.92 (d, J=8.3, 2H), 4.31 (q, J=7.1, 2H), 1.28 (t, J=7.0, 3H). MS (DCI+) m/z 286 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[C:3]=1[CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[BH4-].[Na+].C([O-])(O)=O.[Na+].[C:25](Cl)(=[O:29])[CH:26]([CH3:28])[CH3:27]>CO.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][NH:9][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[C:3]=1[CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1
Reactant: CC(C)C(=O)Cl
Reactant: N#Cc1nccc(Cl)c1COC1CCCCO1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)C(=O)NCc1nccc(Cl)c1COC1CCCCO1

Procedure:
4-Chloro-3-(tetrahydro-pyran-2-yloxymethyl)-pyridine-2-carbonitrile (30 mg. 0.12 mmol) was dissolved in a mixture of MeOH (0.75 mL) and THF (1 mL). CoCl2 hexahydrate (56 mg. 0.24 mmol) and NaBH4 (45 mg. 1.19 mmol dissolved in 1 mL MeOH) were added. After stirring for 8 min at RT sat. NaHCO3 solution (1 mL) and isobutyryl chloride (125 μL. 1.19 mmol) were added. The solvents were removed in vacuo and the residue was partioned between sat. NH4Cl solution (10 mL) and DCM (10 mL) and extracted with DCM (3×10 ml). The combined organic layers were washed with brine and dried over Na2SO4 filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with hexane/EtOAc 2:1→1:2) to give the title compound. MS (m/z): 326.8 [M+H+]
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[C:6]([NH:8][C:9]1[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:7])#[N:2].[CH2:19]([O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)[CH3:20]>C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[C:6]([NH:8][C:9]1[C:10]([NH:15][C:26](=[O:27])[C:25]2[CH:24]=[CH:23][C:22]([O:21][CH2:19][CH3:20])=[CH:30][CH:29]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:7])#[N:2]
Reactant: N#Cc1cccc(C(=O)Nc2ccccc2N)c1
Reactant: CCOc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Product: CCOc1ccc(C(=O)Nc2ccccc2NC(=O)c2cccc(C#N)c2)cc1

Procedure:
Using a procedure similar to 1B except starting with N1-(3-cyanobenzoyl)-1,2-benzenediamine, 4-ethoxybenzoyl chloride and triethylamine as base, the title compound was obtained as a white solid (39%); mp: 168-9° C.; IR(KBr): 1645, 1672, 2231, 3377 cm−1; MS(FD): 385(M+).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[C:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26]Br)=[CH:18][CH:17]=1)#[N:15]>CC(C)=O>[C:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][N:2]2[N:3]=[N:4][CH:5]=[N:1]2)=[CH:18][CH:17]=1)#[N:15]
Reactant: N#Cc1ccc(CBr)c2ccccc12
Reactant: c1nnn[nH]1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(Cn2ncnn2)c2ccccc12
Reaction time: 3.5 h

Procedure:
420 mg of tetrazole, 553 mg of potassium carbonate and 53 mg of potassium iodide are added to a solution of 985 mg of 1-cyano-4-bromomethyl-naphthalene in 20 ml acetone, and the mixture is stirred for 3.5 hours at 45°. After the reaction mixture has cooled, the solvent is distilled off and the residue is dissolved in methylene chloride. The organic solution is washed with water and brine, then dried over sodium sulfate and concentrated. Separation by column chromatography yields first, by elution with toluene/ethyl acetate (9:1), 1-cyano-4-(2-tetrazolyl)methyl-naphthalene, m.p. 124°, [IR(CH2Cl2): 3052, 2225, 1592, 1516 cm-1, 1H-NMR (DMSO-d6): δ=6.62 (2H, s), 7.6 and 8.2 (2H, m), 7.83 (2H, m), 8.2 and 8.33 (2H, m), 9.02 (1H, s) ppm] and then, with toluene/ethyl acetate (3:1), 1-cyano- 4-(1-tetrazolyl)methylnaphthalene, m.p. 171° [IR(CH2Cl2): 3050, 2227, 1516, 1482 cm-1 ; 1H-NMR (DMSO-d6): δ=6.36 (2H, s), 7.5 and 8.2 (2H, m), 7.85 (2H, m), 8.2 and 8.37 (2H, m), 9.6 (1H, s) ppm.
Reaction SMILES: [C:1]([OH:10])(=O)[CH:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5].S(Cl)([Cl:13])=O>C1C=CC=CC=1>[C:1]([Cl:13])(=[O:10])[CH:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5]
Reactant: O=S(Cl)Cl
Reactant: CCCC(CCC)C(=O)O
Solvent: c1ccccc1
Product: CCCC(CCC)C(=O)Cl
Temperature: 50 °C

Procedure:
To 4.32 g (30 mmol) of valproic acid in an ice bath, thionyl chloride (3.60 g, 30 mmol) was slowly added, with stirring. The neat mixture was allowed to come to room temperature and then heated in a water bath at 50° C. for 30 minutes. 50 ml portions of dry benzene were twice added and removed under reduced pressure. The resultant product was used in subsequent reactions without further purification.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]1([CH2:13][N:14]2[C:18](=[O:19])[CH:17]([CH2:20][CH2:21][CH3:22])[NH:16][S:15]2(=[O:24])=[O:23])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CI>C1COCC1>[C:7]1([CH2:13][N:14]2[C:18](=[O:19])[CH:17]([CH2:20][CH2:21][CH3:22])[N:16]([CH3:1])[S:15]2(=[O:23])=[O:24])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)[O-]
Reactant: CCCC1NS(=O)(=O)N(Cc2ccccc2)C1=O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CCCC1C(=O)N(Cc2ccccc2)S(=O)(=O)N1C
Reaction time: 1 h
Yield: 95 %

Procedure:
Potassium t-butoxide (1.05 g, 9.37 mmol) was added to a solution of 2-phenylmethyl-4-propyl-1,2, 5-thiadiazolidin-3-one 1,1-dioxide (2.4 g, 8.95 mmol) in 25 ml of THF at 0° C. and the mixture was stirred at this temperature for 1 hour. To the mixture was added methyl iodide (6.35 g, 44.73 mmol) and the resulting mixture was allowed to stir at 0° C. for 0.5 hour and at room temperature for 4 hours. The resulting mixture was quenched with saturated ammonium chloride, extracted with ethyl acetate and the organic layer was washed with brine. The organic layer was dried, concentrated in vacuo, and the residue was purified by flash chromatography to afford 2.4 g (95%) of 2-phenylmethyl-4-propyl-5-methyl-1,2,5-thiadiazol-idin-3-one 1,1-dioxide (Formula XI: R1 =H; R2 =propyl; R3 =CH3) as an oil.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.Cl.[CH2:19]([O:26][CH:27]1[CH2:30][NH:29][CH2:28]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH2:19]([O:26][CH:27]1[CH2:28][N:29]([C:15](=[O:17])/[CH:14]=[CH:13]/[C:8]2[CH:7]=[C:6]3[C:11](=[N:10][CH:9]=2)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]3)[CH2:30]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: c1ccc(COC2CNC2)cc1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1CCc2cc(/C=C/C(=O)N3CC(OCc4ccccc4)C3)cnc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (60 mg, 0.24 mmol), DMF (5.8 mL), 3-(benzyloxy)azetidine hydrochloride (58 mg, 0.29 mmol; which may be prepared as described in Step 2), DIPEA (96 μL, 0.58 mmol), DMAP (2.4 mg, 0.02 mmol) and EDAC (56 mg, 0.29 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was purified by precipitation in MeOH/H2O and then triturated in acetone/diethyl ether to give the title compound as a beige solid (33 mg, 38%).
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27](O)=[O:28])[CH:22]=3)[CH:17]=1)[CH2:12]2.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]([CH2:39][OH:40])[CH2:31]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[OH:40][CH2:39][CH:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:30]([C:27]([C:23]2[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[CH2:12][C:4]3([C:5]5[C:6](=[N:7][CH:8]=[CH:9][CH:10]=5)[NH:11][C:3]3=[O:2])[CH2:19]4)[CH:22]=2)=[O:28])[CH2:31]1
Reactant: OCC1CNc2ccccc21
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1)N1CC(CO)c2ccccc21

Procedure:
100 mg (0.24 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 45 mg (0.30 mmol) (2,3-dihydro-1H-indol-3-yl)-methanol, 0.10 mL (0.71 mmol) TEA and 88 mg (0.27 mmol) TBTU in 1.0 mL DMF were stirred overnight at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and the solvent was evaporated down by about half. The precipitate formed was suction filtered and dried.
Reaction SMILES: [CH2:1]([NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(N(CC)CC)C.C1(N(C2CCCCC2)[C:27](=[O:36])[C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[C:30](C)[CH:29]=2)CCCC1>C1COCC1>[CH2:1]([N:7]([CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1)[C:27](=[O:36])[C:28]1[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: Cc1cc(C(=O)N(C2CCCCC2)C2CCCC2)ccc1Br
Reactant: CCCCCCNC1CCCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCN(C(=O)c1ccc(Br)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold (0° C. to 5° C.) stirred solution of N-n-hexyl-N-cyclohexyl amine (4.40 g, 24 mmol) and triethylamine (2.5 g, 24 mmol) in dry THF (50 mL) is added dropwise a solution of acid chloride (5.0 g, 23 mmol) in THF (20 mL). The reaction is stirred at room temperature overnight and worked up in the same manner as for 4-bromo-3-methylbenzoic acid N-cyclopentyl-N-cyclohexyl amide. The crude product is purified by either recrystallization or by chromatography on silica gel using mixtures of ethyl acetate and hexane as eluents.
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([OH:9])[C:5]([F:8])([F:7])[F:6].[F:10][C:11]1[C:12](F)=[C:13]([F:23])[C:14]([F:22])=[C:15]2C(=O)[O:19][C:17](=[O:18])[C:16]=12>O>[F:6][C:5]([F:8])([F:7])[CH2:4][O:9][C:12]1[C:11]([F:10])=[C:16]([CH:15]=[C:14]([F:22])[C:13]=1[F:23])[C:17]([OH:19])=[O:18]
Reactant: OCC(F)(F)F
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(F)c(F)c(OCC(F)(F)F)c1F
Temperature: 70 °C
Yield: 51 %

Procedure:
An initial charge comprising a mixture of 7.6 g of water, 2.1 g of lithium hydroxide hydrate, 10 g of trifluoroethanol and 2.2 g (10 mmol) of tetrafluorophthalic anhydride is heated at 70° C. for 96 hours, after which the content of tetrafluorophthalic anhydride has fallen to below 1% (GC). The procedure described in Example 3 is then followed to give 1.4 g (5.1 mmol, corresponding to 51%) of 3-trifluoroethoxy-2,4,5-trifluorobenzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=3)[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:9][N:8]2[CH:27]=1)=[O:4].[NH:28]1[CH2:31][CH:30]([C:32]2[NH:36][N:35]=[C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[N:38]=3)[N:33]=2)[CH2:29]1>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][N:28]4[CH2:31][CH:30]([C:32]5[N:33]=[C:34]([C:37]6[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[N:38]=6)[NH:35][N:36]=5)[CH2:29]4)=[CH:15][CH:14]=3)[C:10]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:9][N:8]2[CH:27]=1)=[O:4]
Reactant: Cc1cccc(-c2n[nH]c(C3CNC3)n2)n1
Reactant: COC(=O)c1cn2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Product: COC(=O)c1cn2cc(-c3ccccc3)c(-c3ccc(CN4CC(c5n[nH]c(-c6cccc(C)n6)n5)C4)cc3)nc2n1
Yield: 9.7 %

Procedure:
The title compound has been prepared in analogy to the aforementioned descriptions by reacting 500 mg (1.4 mmol) 7-(4-formylphenyl)-6-phenyl-imidazo[1,2-a]pyrimidine-2-carboxylic acid methyl ester with 671.9 mg (1.4 mmol) 2-(5-azetidine-3-yl-[1,2,4]triazole-3-yl)-6-methylpyridine×2HCl (60% pure), yielding 75.6 mg (9.2%) of the desired product after purification.