Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Br)[CH:5]=1.Cl.[CH3:14][NH:15][CH3:16].C(N(CC)CC)C>CCOCC>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:15]([CH3:16])[CH3:14])[CH:5]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: CNC
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(CN(C)C)c1
Temperature: 25 °C
Yield: 55.4 %

Procedure:
To a cooled (−10° C.) solution of methyl-3-(bromomethyl)benzoate (22.9 g, 100 mmol) in ether (250 ml) was added dimethylamine hydrochloride salt (17.9 g, 220 mmol) followed by slow addition of triethylamine (30.6 ml, 220 mmol). The mixture was then allowed to warm to r.t. over 48 h, the solids were filtered off and the filter-cake washed with ether. The yellow oil remaining after evaporation of the solvent was distilled over a Vigreux column to afford the title compound (10.7 g, 55% yield) as a colorless oil. MS: m/e=193 (M+).
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.Cl[C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:31])([CH3:30])[C:27]([OH:29])=[O:28])=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+].Cl>O1CCOCC1.O>[CH3:31][C:26]([C:23]1[CH:24]=[CH:25][C:20]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][N:4]3[CH2:5][CH2:6][CH2:7][C@H:3]3[CH3:2])=[CH:11][CH:12]=2)=[CH:21][CH:22]=1)([CH3:30])[C:27]([OH:29])=[O:28]
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Reactant: C[C@@H]1CCCN1CCc1ccc(B(O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(C(C)(C)C(=O)O)cc2)cc1
Temperature: 150 °C

Procedure:
A mixture of (R)-4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenylboronic acid hydrochloride (50.9 mg, 0.189 mmol), 2-(4-chlorophenyl)-2-methylpropanoic acid (50 mg, 0.252 mmol), Na2CO3 (107 mg, 1.007 mmol), and dichlorobis(p-dimethylaminophenyldi-tert-butylphosphine)palladium (1.782 mg, 2.52 μmol) in 1,4-dioxane (1 mL) and H2O (0.2 mL) was heated under microwave irradiation at 150° C. for 10 min. To the resulting mixture was added 2 M HCl (8 mL) and extracted with 5% EtOAc/hexane (10 mL). To the aqueous phase was added ACN (2 mL) to dissolve the solid precipitates. The mixture was purified by HPLC. LCMS m/z=352.4 [M+H]+; 1H NMR (400 MHz, CD3CN) δ ppm 1.12 (d, J=13.6 Hz, 0.4H), 1.35 (d, J=6.4 Hz, 2.6H), 1.48 (s, 6H), 1.57-1.72 (m, 1H), 1.89-2.00 (m, 2H), 2.09-2.21 (m, 1H), 2.93-3.11 (m, 4H), 3.22-3.35 (m, 1H), 3.37-3.48 (m, 1H), 3.62-3.75 (m, 1H), 7.27 (d, J=8.1 Hz, 2H), 7.37 (d, J=8.3 Hz, 2H), 7.51 (d, J=8.2 Hz, 2H), 7.52 (d, J=7.9 Hz, 2H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[F:44][C:45]1[CH:46]=[C:47]([CH2:52][C:53](O)=[O:54])[CH:48]=[C:49]([F:51])[CH:50]=1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[F:44][C:45]1[CH:46]=[C:47]([CH2:52][C:53]([NH:2][CH2:3][C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:5]=2[C:6](=[O:22])[N:7]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:8]3=[O:13])=[O:54])[CH:48]=[C:49]([F:51])[CH:50]=1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(Cc1cc(F)cc(F)c1)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 51.5 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 3,5-difluorophenylacetic acid (0.4 g, 2.4 mmol) were added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight. The resulting suspension was filtered, and the solid was reslurried in hot acetone (15 mL) to afford 2-(3,5-difluoro-phenyl)-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-acetamide (0.5 g, 56%) as a white solid: mp, 238-240° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.63 min. (97%); 1H NMR (DMSO-d6) δ 2.02-2.07 (m, 1H), 2.51-2.63 (m, 2H), 2.84-2.96 (m, 1H), 3.60 (s, 2H), 4.73 (d, J=5.8 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.7 Hz, 1H), 6.89-7.14 (m, 3H), 7.65-7.84 (m, 3H), 8.70 (t, J=5.8 Hz, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 21.94, 30.90, 37.91, 41.41, 48.83, 101.62 (101.95, 102.30), 112.18 (112.28, 112.41, 112.51), 121.95, 127.16, 131.52, 133.29, 134.68, 138.91, 140.24 (140.37, 140.50), 160.39 (160.57, 163.64, 163.82), 166.88, 167.41, 169.53, 169.77, 172.72; Anal. Calcd. for C22H17N3O5F2: C, 59.87; H, 3.88; N, 9.52; F, 8.61. Found: C, 59.66; H, 3.83; N, 9.77; F, 8.47.
Reaction SMILES: [H-].[Na+].[I-].[C:4]([C:6]1[CH:28]=[CH:27][CH:26]=[CH:25][C:7]=1[CH2:8][O:9][C:10]1[C:11]2[N:12]([C:16]([CH2:20][N+](C)(C)C)=[C:17]([CH3:19])[N:18]=2)[CH:13]=[CH:14][CH:15]=1)#[N:5]>C(O)C#C>[C:4]([C:6]1[CH:28]=[CH:27][CH:26]=[CH:25][C:7]=1[CH2:8][O:9][C:10]1[C:11]2[N:12]([C:16]([CH2:20][O:9][CH2:8][C:7]#[CH:6])=[C:17]([CH3:19])[N:18]=2)[CH:13]=[CH:14][CH:15]=1)#[N:5]
Reactant: Cc1nc2c(OCc3ccccc3C#N)cccn2c1C[N+](C)(C)C
Agent: C#CCO
Agent: [H-]
Agent: [I-]
Product: C#CCOCc1c(C)nc2c(OCc3ccccc3C#N)cccn12
Temperature: 0 °C
Reaction time: 2 h
Yield: 141.4 %

Procedure:
To a solution of sodium hydride (60% in mineral oil dispersion, 0.14 g) in 2-propynyl alcohol (6 ml) was added 8-(2-cyanobenzyloxy)-3-trimethylammoniomethyl-2-methylimidazo[1,2-a]pyridine iodide (1.5 g) and the mixture was heated at 90°-95° C. with stirring for 2 hours. After being cooled, the mixture was poured into ice-water and the resulting precipitate was collected by filtration and dissolved in methylene chloride. The solution was treated successively with silica gel (1 g) and activated charcoal and evaporated in vacuo. The crystalline residue was recrystallized from a mixture of methylene chloride and n-hexane to give 8-(2-cyanobenzyloxy)-2-methyl-3-(2-propynyloxymethyl)imidazo[1,2-a]pyridine (0.76 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[Cl-].[CH:12](=[N+:19]([CH3:21])[CH3:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:20][N:19]([CH3:21])[CH:12]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[N+](C)=Cc1ccccc1
Reactant: Cn1ccc2ccccc21
Agent: [Cl-]
Product: CN(C)C(c1ccccc1)c1cn(C)c2ccccc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-methyl-1H-indole and benzylidene-dimethyl-ammonium chloride, which had been prepared in accordance with example 1.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([NH2:12])=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[C:15]1[C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[F:26])[CH3:2].N([O-])=O.[Na+].[N-:31]=[N+:32]=[N-].[Na+]>C(O)(=O)C.O>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([N:12]=[N+:31]=[N-:32])=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[C:15]1[C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[F:26])[CH3:2]
Reactant: CCn1c(Cn2ccnc2-c2cc(F)ccc2F)nc2cc(N)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCn1c(Cn2ccnc2-c2cc(F)ccc2F)nc2cc(N=[N+]=[N-])ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cold solution of 1-ethyl-2-{[2-(2,5-difluorophenyl)-1H-imidazol-1-yl]methyl}-5-amino-1H-benzimidazole (466 mg) in acetic acid (8 mL) a solution of sodium nitrite (1.1 eq) in water (4 mL) is added dropwise. After stirring at 0° C. for 1 h, a solution of sodium azide (1.3 eq) in water (5 mL) is added dropwise. Stirring is continued for 0.5 h at 0° C., and then at room temperature for 0.5 h. The reaction mixture is concentrated to ⅓ volume, water (10 mL) is added and then mixture is then extracted with ethyl acetate (3×). The combined organic layers are washed with aqueous sodium bicarbonate (2×), then washed with saturated aqueous sodium chloride, dried (MgSO4), and concentrated to give 641 mg of crude 1-Ethyl-2-{[2-(2,5-difluorophenyl)-1H-imidazol-1-yl]methyl}-5-azido-1H-benzimidazole.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])[CH:5]=[CH:4][N:3]=[CH:2]1.I.CS[C:18]1[C:26]2[CH:27]=[CH:28][CH:29]=[C:24]3[C:25]=2[C:20](=[CH:21][CH:22]=[CH:23]3)[N:19]=1.[ClH:30]>C(O)C>[ClH:30].[ClH:30].[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:18]2[C:26]3[CH:27]=[CH:28][CH:29]=[C:24]4[C:25]=3[C:20](=[CH:21][CH:22]=[CH:23]4)[N:19]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NCCCCCCCCn1ccnc1
Reactant: CSC1=Nc2cccc3cccc1c23
Agent: Cl
Agent: I
Solvent: CCO
Product: c1cc2c3c(cccc3c1)C(NCCCCCCCCn1ccnc1)=N2

Procedure:
A mixture of 2.1 of 8-(1H-imidazol-l-yl)octanamine, 400 ml of ethanol, and 3.2 g of 2-(methylthio)benz(cd)indole hydriodide was reacted as described in Example 19, giving the base derivative which was then treated with hydrochloric acid giving 1.3 g of the desired hydrochloride salt, mp 222° C.-224° C.
Reaction SMILES: [N:1]1([C:6]2[N:15]=[C:14]([NH:16][CH2:17][CH2:18][O:19][CH3:20])[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:21]#[C:22][Si](CC)(CC)CC)[CH:12]=3)[N:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:21]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[N:15]=[C:14]2[NH:16][CH2:17][CH2:18][O:19][CH3:20])#[CH:22]
Reactant: CC[Si](C#Cc1ccc2nc(-n3ccnc3)nc(NCCOC)c2c1)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc2nc(-n3ccnc3)nc(NCCOC)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.4 %

Procedure:
To 1.35 g of the compound prepared in example 17 in 20 mL of THF was added 3.3 mL of tetrabutylammonium fluoride (1M in THF). Stirred at room temperature for 1.5 hrs. The excess THF was removed under reduced pressure and the residue taken up in chloroform and water. The insoluble precipitate was collected by filtration. Yielded 0.83 g of the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.[NH:23]1[CH2:27][CH2:26][C@H:25]([O:28][CH2:29][CH2:30][C:31]#[N:32])[CH2:24]1>>[Cl:22][C:7]1[C:8]([NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:23]1[CH2:27][CH2:26][C@H:25]([O:28][CH2:29][CH2:30][C:31]#[N:32])[CH2:24]1)[CH:11]=[CH:10]2
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Reactant: N#CCCO[C@H]1CCNC1
Product: N#CCCO[C@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Yield: 70.7 %

Procedure:
Prepared according to the method of example 30, using N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (prepared as in Example 1(a)) (400 mg) and 3-[(3S)-3-pyrrolidinyloxy]-propanenitrile (Example 107 (b)) (350 mg). The resulting precipitate was collected by filtration and washed with acetonitrile to give the sub-title compound as a solid (370 mg).
Reaction SMILES: C([O:8][C:9]([C:11]1[C:20]2[C:15](=[C:16]([F:21])[CH:17]=[CH:18][CH:19]=2)[C:14](=[O:22])[N:13]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[C:12]=1[CH3:29])=[O:10])C1C=CC=CC=1>CO.[Pd]>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[C:14](=[O:22])[N:13]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[C:12]([CH3:29])=[C:11]2[C:9]([OH:10])=[O:8]
Reactant: Cc1c(C(=O)OCc2ccccc2)c2cccc(F)c2c(=O)n1-c1cccnc1
Agent: [Pd]
Solvent: CO
Product: Cc1c(C(=O)O)c2cccc(F)c2c(=O)n1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
8-Fluoro-3-methyl-1-oxo-2-pyridin-3-yl-1,2-dihydro-isoquinoline-4-carboxylic acid benzyl ester (0.150 g, 0.386 mmol) was dissolved in methanol (2 mL) and added to 10% Palladium on Charcoal (10 mg). The reaction mixture was stirred under an atmosphere of hydrogen for 60 minutes at room temperature. The reaction mixture was filtered and was rotovaped to give the title compound (0.105 g; yield 91.2%) as a yellow oil. Alternatively, the title acid can be obtained directly under the same conditions according to the above described Pd-catalysed carbonylation in the presence of water instead of benzyl alcohol. LC-MS (m/z) 299.3 (MH+); tR=0.43. 1H NMR (500 MHz, CDCl3): 2.15 (s, 3H), 7.16 (m, 1H), 7.59 (m, 1H), 7.61-7.7 (m, 2H), 7.73 (m, 1H), 8.6 (br. s, 1H), 8.78 (br., 1H).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([NH2:10])[C:4]=2[CH:3]=[N:2]1.I[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1>>[N:15]1[CH:16]=[CH:17][C:12]([N:1]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([NH2:10])[C:4]=3[CH:3]=[N:2]2)=[CH:13][CH:14]=1
Reactant: Nc1cccc2[nH]ncc12
Reactant: Ic1ccncc1
Product: Nc1cccc2c1cnn2-c1ccncc1

Procedure:
Similarly prepared to intermediate 1 from 1H-indazol-4-amine and 4-iodopyridine.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[O:7]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[C:24]1[C:25]([NH2:31])=[N:26][CH:27]=[C:28]([F:30])[CH:29]=1>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:30][C:28]1[CH:29]=[C:24]([C:17]2[CH:18]=[CH:19][C:14]([O:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:15][CH:16]=2)[C:25]([NH2:31])=[N:26][CH:27]=1
Reactant: Nc1ncc(F)cc1Br
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1ncc(F)cc1-c1ccc(Oc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
A mixture of sodium carbonate (122 mg), tetrakis(triphenylphosphine)palladium(0) (33.2 mg), 4-phenoxyphenylboronic acid (160 mg) and 3-bromo-5-fluoropyridin-2-amine (110 mg) in DME (10 mL) and water (3 mL) was stirred at 80° C. overnight. The mixture was added with silica gel, concentrated in vacuo, and purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (132 mg) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Cl[C:28]1[N:32]([CH3:33])[C:31]2[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=2[N:29]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:28]5[N:32]([CH3:33])[C:31]6[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=6[N:29]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: Cn1c(Cl)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5nc6ccccc6n5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-chloro-1-methyl-1H-benzoimidazole following a procedure analogous to that described for Intermediate 12; K2CO3 and acetonitrile are used as base and solvent, respectively, at 110° C. LC (method 4): tR=0.72 min; Mass spectrum (ESI+): m/z=489 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:22])[C@H:4]([CH:19]([CH3:21])[CH3:20])[NH:5][C:6]([N:8]([CH3:18])[CH2:9][C:10]1[N:11]=[C:12]([CH:15]([CH3:17])[CH3:16])[O:13][CH:14]=1)=[O:7]>O1CCOCC1.O>[CH3:18][N:8]([C:6]([NH:5][C@H:4]([C:3]([OH:22])=[O:2])[CH:19]([CH3:20])[CH3:21])=[O:7])[CH2:9][C:10]1[N:11]=[C:12]([CH:15]([CH3:17])[CH3:16])[O:13][CH:14]=1
Reactant: COC(=O)[C@@H](NC(=O)N(C)Cc1coc(C(C)C)n1)C(C)C
Solvent: C1COCCO1
Solvent: O
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)co1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To a solution of N-((N-methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)-L-valine methyl ester 10 (0.511 g, 0.00164 mol) in p-dioxane (10 mL) and H2O (5 mL) was added LiOH monohydrate (0.103 g, 0.00246 mol). After stirring at room temperature for 1 hr, the p-dioxane was removed by rotary evaporation in vacuo, and the remaining aqueous solution was treated with 1N aq HCl (2.46 mL) and extracted with ethyl acetate (4×100 mL). The combined organic extract was washed with saturated brine and dried for 15 mins over Na2SO4. Concentration in vacuo followed by CH2Cl2 chases (2x) afforded the desired compound as a white solid (0.480 g, 0.00161 mol, 98%): 1H NMR (DMSO-d6) δ 0.90 (dd, J1 =6.9 Hz, J2 =2.4 Hz, 6H), 1.24 (d, J=6.9 Hz, 6H), 1.99-2.12 (m, 1H), 2.83 (s, 3H), 2.96-3.10 (m, 1H), 3.96 (dd, J1 =8.4 Hz, J2 =6 Hz, 1H), 4.19-4.32 (m, 2H), 6.26 (d, J=8.4 Hz, 1H), 7.80 (s, 1H). Mass spectrum: (M+H)+ =298
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[CH3:15][N:16]([C:29]1[S:30][C:31]([C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)=[N:32][N:33]=1)[C:17](=[O:28])[CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C>ClCCl>[NH2:20][CH2:19][CH2:18][C:17]([N:16]([CH3:15])[C:29]1[S:30][C:31]([C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)=[N:32][N:33]=1)=[O:28]
Reactant: CN(C(=O)CCNC(=O)OC(C)(C)C)c1nnc(-c2cccnc2)s1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)CCN)c1nnc(-c2cccnc2)s1
Temperature: 23 °C
Yield: 49.5 %

Procedure:
Triethylsilane (530 μL, 3.3 mmol, 5.0 equiv) and trifluoroacetic acid (4.9 mL, 66 mmol, 100 equiv) were sequentially added to a stirred solution of tert-butyl 3-(methyl(5-(pyridin-3-yl)-1,3,4-thiadiazol-2-yl)amino)-3-oxopropylcarbamate (240 mg, 0.66 mmol, 1.0 equiv) in dichloromethane (8.8 mL) at 23° C. The resulting colorless solution was stirred at 23° C. for 30 m. The reaction mixture was concentrated by rotary evaporation. The residue was diluted with a saturated solution of sodium bicarbonate (80 mL) and extracted with dichloromethane (8×50 mL). The combined organic layers were dried (Na2SO4), gravity filtered, and concentrated by rotary evaporation to afford the title compound as a tan powder (86 mg, 49%): mp 110-112° C.; IR (KBr thin film) 3047 (w), 2926 (w), 1682 (s), 1591 (m) cm−1; 1H NMR (300 MHz, CDCl3) δ 9.15 (d, J=2 Hz, 1H), 8.69 (dd, J=5, 2 Hz, 1H), 8.28 (dt, J=8, 2 Hz, 1H), 7.43 (dd, J=8, 5 Hz, 1H), 3.86 (s, 3H), 3.17 (m, 2H), 2.86 (t, J=6 Hz, 2H); ESIMS m/z 264 ([M+H]+).
Reaction SMILES: [F:1][C:2]([F:13])([S:9]([O-:12])(=[O:11])=[O:10])[CH:3]([OH:8])[C:4]([F:7])([F:6])[F:5].[CH2:14]([N+:21]([CH3:24])([CH3:23])[CH3:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:25]12([C:35](Cl)=[O:36])[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2>>[C:25]12([C:35]([O:8][CH:3]([C:4]([F:6])([F:5])[F:7])[C:2]([F:1])([F:13])[S:9]([O-:12])(=[O:10])=[O:11])=[O:36])[CH2:32][CH:31]3[CH2:30][CH:29]([CH2:28][CH:27]([CH2:33]3)[CH2:26]1)[CH2:34]2.[CH2:14]([N+:21]([CH3:24])([CH3:23])[CH3:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)([O-])C(F)(F)C(O)C(F)(F)F
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: C[N+](C)(C)Cc1ccccc1
Product: O=C(OC(C(F)(F)F)C(F)(F)S(=O)(=O)[O-])C12CC3CC(CC(C3)C1)C2

Procedure:
Benzyltrimethylammonium 1,1,3,3,3-pentafluoro-2-hydroxypropane-1-sulfonate in Synthesis Example 1-1 and 1-adamantanecarboxylic acid chloride were reacted in accordance with the teaching of JP-A 2008-106045, yielding the desired compound, benzyltrimethylammonium 2-(adamantane-1-carbonyloxy)-1,1,3,3,3-pentafluoropropane-1-sulfonate as white crystals.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[C:20]([O:25]C)[CH:19]=[C:18]3[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=2)([C:9]2[N:10]([CH3:14])[CH:11]=[N:12][CH:13]=2)[OH:8])=[CH:4][CH:3]=1.Cl>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]([OH:8])([C:9]2[N:10]([CH3:14])[CH:11]=[N:12][CH:13]=2)[C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20](=[O:25])[CH:19]=[C:18]3[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(-c2cc(OC)nc3ccc(C(O)(c4ccc(Cl)s4)c4cncn4C)cc23)c1
Agent: Cl
Solvent: C1CCOC1
Product: COc1cccc(-c2cc(=O)[nH]c3ccc(C(O)(c4ccc(Cl)s4)c4cncn4C)cc23)c1
Yield: 100.1 %

Procedure:
Following the same procedure as described in example 1F (5-chloro-thiophen-2-y)-[4-(3-methoxy-phenyl)-2-methoxy-quinolin-6-yl]-(3-methyl-3H-imidazol-4-yl)-methanol (1.14 g, 2.34 mmol) was treated with HCl in aqueous THF to yield the title compound of 31B (1.12 g, 100% yield).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.S(Cl)(Cl)=O.C1(C)C=CC=CC=1.[NH2:25][C:26]1[CH:27]=[C:28]([CH:45]=[CH:46][CH:47]=1)[O:29][C:30]1[CH:44]=[CH:43][C:33]2[N:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[S:36][C:32]=2[CH:31]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH:40]1([C:38]([NH:37][C:35]2[S:36][C:32]3[CH:31]=[C:30]([O:29][C:28]4[CH:27]=[C:26]([NH:25][C:6](=[O:8])[C:5]5[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:13])[F:12])[CH:4]=5)[CH:47]=[CH:46][CH:45]=4)[CH:44]=[CH:43][C:33]=3[N:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)sc3c2)c1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)sc3c2)c1)c1cccc(C(F)(F)F)c1
Yield: 76.3 %

Procedure:
Using 3-(trifluoromethyl)benzoic acid (182 mg, 959 μmol), thionyl chloride (0.4 mL, 5.48 mmol), toluene (5 mL), N-[6-(3-aminophenoxy)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (129 mg, 395 μmol) produced in Example A1(vii), pyridine (5 mL), and N,N-dimethylpyridine-4-amine (21.3 mg, 176.0 μmol) as starting materials, and in the same manner as in Example A1(viii), the title compound (150 mg, 76%) was obtained as a colorless amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8]C.N1CCOCC1.C1(N=C=O)C=CC=CC=1>C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[OH:8]
Reactant: COc1cnnc(Cl)c1OC
Solvent: C1COCCN1
Solvent: O=C=Nc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cnnc(Cl)c1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
3-Chloro-4,5-dimethoxypyridazine (17.0 g) and morpholine (59.0 mL) were stirred at 100° C. for 2 hr, and cooled to 0° C. To the reaction mixture was added phenyl isocyanate (73.8 mL) at 0° C., and the mixture was stirred at the same temperature for 30 min, and diluted with ethyl acetate. The resulting solid was removed by filtration. The filtrate was concentrated, and the residue was purified by column chromatography (ethyl acetate/hexane-methanol/ethyl acetate) to give the title compound (9.61 g).
Reaction SMILES: [C:1]1([N:7]2[N+:11]([O-])=[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>>[C:1]1([N:7]2[N:8]=[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]3=[N:11]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: [O-][n+]1c2ccccc2nn1-c1ccccc1
Product: c1ccc(-n2nc3ccccc3n2)cc1

Procedure:
A 2-phenylbenzotriazole-N-oxide which is the chosen starting material is dissolved in a solvent contained in a reaction vessel into which a hydrogenation catalyst and a basic substance are then placed. After the air in the reaction vessel has been replaced by hydrogen, a given amount of hydrogen is charged into the reaction vessel, and the reaction is then allowed to proceed under atmospheric pressure or a given pressure at a temperature of room temperature to 170° C. under agitation. After the reaction has been completed, the catalyst is filtered off, the solvent layer is washed with water, and the solvent is distilled off. The crude product is then purified by recrystallization to obtain the corresponding 2-phenylbenzotriazole as a pure product.