Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]([C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])[CH2:4][CH2:3][C:2]1=[O:14].C(=O)([O-])[O-].[K+].[K+].[Cl:21][CH2:22][C:23](Cl)=[O:24]>C(Cl)Cl>[NH:1]1[CH:5]([C:6]([N:8]2[CH2:9][CH2:10][N:11]([C:23](=[O:24])[CH2:22][Cl:21])[CH2:12][CH2:13]2)=[O:7])[CH2:4][CH2:3][C:2]1=[O:14]
Reactant: O=C1CCC(C(=O)N2CCNCC2)N1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C1CCC(C(=O)N2CCN(C(=O)CCl)CC2)N1
Temperature: 0 °C
Yield: 73 %

Procedure:
A mixed solution of 2.3 g of N-(2-pyrrolidone-5-carbonyl)piperazine, 50 ml of methylene chloride, and 2.8 g of anhydrous potassium carbonate was cooled with ice water and 1.3 g of chloro acetyl chloride was dropped therein with stirring. After the dropping, the mixture was stirred for another 1 hour at room temperature. The insoluble matter was removed by filtration and the solvent was evaporated in vacuo from the filtrate to give 2.3 g of oily N-(2-pyrrolidone-5-carbonyl)-N'-chloroacetylpiperazine. This was dissolved in 15 ml of N,N-dimethylformamide and 0.8 g of morpholine and 2.2 g of anhydrous potassium carbonate were added thereto, and the mixture was heated at 80° C. for 3 hours with stirring. The insoluble matter was filtered off therefrom and the solvent was evaporated in vacuo from the filtrate. The residue was purified by a silica gel column chromatography to give 2.5 g of the product. This was recrystallized from a mixture of methanol and ethyl ether to give 2.1 g of desired product, m.p. 204°-205° C.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[C:16]2[O:15][CH:14]=[CH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.[CH3:17][S:18]SC.O>O1CCCC1>[CH3:6][O:7][C:8]1[C:16]2[O:15][C:14]([S:18][CH3:17])=[CH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: CSSC
Reactant: COc1cccc2ccoc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2cc(SC)oc12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (1.6M in hexanes, 10.2 ml) was added dropwise to a cooled (-78° C.) solution of 7-methoxybenzofuran (2.0 g) in tetrahydrofuran (40 ml) under an inert atmosphere. Methyl disulfide (1.46 ml) was added and the reaction mixture was stirred at -78° C. for 30 minutes, then at room temperature for 1 h. Water was added and the tetrahydrofuran was removed in vacuo. The aqueous residue was extracted with ether (3×100 ml) and the combined organic phases were washed with water (100 ml) and dried over sodium sulfate. The solvent was removed in vacuo to afford the title compound as a yellow oil (2.73 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][CH2:8][C:9]1[N:10]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:11](=[O:32])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([O:24]CC1C=CC=CC=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.C(O)C.[C].[Pd]>[CH2:20]([O:19][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:24])[CH:16]=2)[C:11](=[O:32])[N:10]([CH2:33][CH:34]([CH3:35])[CH3:36])[C:9]=1[CH2:8][NH:7][C:6](=[O:37])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(OCc3ccccc3)cc12
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(O)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
A suspension of tert-butyl(6-benzyloxy-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (6.10 g, 12 mmol) and 5% palladium carbon (2.0 g) in tetrahydrofuran (30 mL) and ethanol (30 mL) was stirred under a hydrogen atmosphere at room temperature for 2 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give tert-butyl (4-butoxy-6-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (4.86 g, 96.8%) as crystals.
Reaction SMILES: [NH2:1][CH:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31])(OCC)=O>O>[C:22]1(=[O:31])[N:1]([CH:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[C:7]([OH:9])=[O:8])[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: CC(C)CC(N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)CC(C(=O)O)N1C(=O)c2ccccc2C1=O
Reaction time: 1 h
Yield: 81.4 %

Procedure:
To a stirred solution of d,1-leucine (3.31 g, 25.0 mmol) and sodium carbonate (2.78 g, 26.25 mmol) in 50 mL of water is added N-carboethoxyphthalimide (5.65 g, 25.0 mmol). After 1 hour at room temperature, the reaction slurry is filtered, the filtrate stirred, and the pH adjusted to 1-2 with 4N hydrochloric acid. The mixture is stirred overnight, the resulting slurry is filtered, and the solid washed with water and dried in vacuo (60° C., <1 mm) to afford 5.32 g (81%) of the 2-phthalimido-4-methylpentanoic acid as a white powder: mp 134°-137° C.; 1H NMR (DMSO-d6, 250 M Hz) δ 12.50 (br s, 1H), 8.00-7.80 (m, 4H), 4.79 (dd, 1H, J=4.3), 2.28-2.10 (m,1H), 1.94-1.77 (m,1H), 1.51-1.134 (m, 1H), 0.89 (d, 3H, J=4.4), 0.86 (d, 3H, J=4.5); 13C NMR (DMSO-d6) δ 170.8, 167.4, 134.8, 131.1, 123.3, 50.2, 36.7, 24.6, 23.0, 20.8. Anal. Calculated for C14H15NO4. Theoretical: C, 64.36; H, 5.74; N, 5.36. Found: C, 64.18; H, 5.73; N, 5.98.
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][CH:8]=[C:9]([I:10])[N:4]2[N:3]=1.[CH3:11][S:12]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)(=[O:14])=[O:13].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[I:10][C:9]1[N:4]2[C:5]([S:6][C:2]([C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([S:12]([CH3:11])(=[O:14])=[O:13])[CH:20]=3)=[N:3]2)=[N:7][CH:8]=1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Brc1nn2c(I)cnc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cccc(-c2nn3c(I)cnc3s2)c1
Temperature: 110 °C
Yield: 37.1 %

Procedure:
A mixture of 2-bromo-5-iodoimidazo[2,1-b][1,3,4]thiadiazole (0.20 g, 0.606 mmol, 1 eq), 3-(methylsulfonyl)phenylboronic acid (0.182 g, 0.909 mmol, 1.5 eq), PdCl2(PPh3)2 (0.085 g, 0.121 mmol, 0.2 eq) and 2M Na2CO3 (1.0 mL) in dioxane (5 mL) was heated at 110° C. for 24 h. More PdCl2(PPh3)2 (0.1 eq) was added and the reaction mixture was heated at 110° C. for 4 h. The solvent was removed, water was added and the mixture was extracted with DCM. The organic layer was dried (MgSO4), filtered and evaporated. The residue was triturated from MeOH and filtered to give the desired product (91 mg, 37%) as an orange solid. It was used in the next step of the synthesis with no further treatment. HPLC-MS (10-95% B in 4 min at 0.5 mL+2 min 100% B, flow 0.8 mL/min, 50° C.): tR=3.98 min, [M+H]+ m/z 405.9.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[S:24][C:25]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:28][C:26]=3[CH:27]=2)[O:21][CH:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[N:19]=[C:20]([C:23]4[S:24][C:25]5[CH:31]=[CH:30][C:29]([C:32]6[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=6)=[CH:28][C:26]=5[CH:27]=4)[O:21][CH:22]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: ClCc1coc(-c2cc3cc(-c4ccccc4)ccc3s2)n1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: c1ccc(-c2ccc3sc(-c4nc(COc5ccc(CCCn6ccnc6)cc5)co4)cc3c2)cc1
Yield: 67 %

Procedure:
In substantially the same manner as in Working Example 109, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-(5-phenyl-2-benzothienyl)oxazole to give 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(5-phenyl-2-benzothienyl)oxazole. The yield was 67%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 168-169° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:37](O)=[O:38])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+:40].N1(O)C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:37]([C@@H:10]1[CH2:11][C@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:17])[CH3:18])[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9]1)(=[O:38])[NH2:40]
Reactant: [NH4+]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nc2cc(F)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(N)=O)CN(C(=O)OC(C)(C)C)C2)nc2cc(F)ccc21
Temperature: 60 °C
Reaction time: 3 h
Yield: 208 %

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[5-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (549 mg), 1H-1,2,3-benzotriazol-1-ol ammonium salt (304 mg) and WSC.HCl (288 mg) were dissolved in DMF (5 ml), diisopropylethylamine (517 μl) was added, and the mixture was stirred at 60° C. for 3 hr. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was diluted with aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (1.14 g).
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[CH3:13][C:14]1[NH:18][C:17]2[CH:19]=[CH:20][C:21]([C:23](O)=[O:24])=[CH:22][C:16]=2[N:15]=1.N>>[ClH:1].[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH:12][C:23]([C:21]3[CH:20]=[CH:19][C:17]4[NH:18][C:14]([CH3:13])=[N:15][C:16]=4[CH:22]=3)=[O:24])[CH2:3]1)[CH2:9]2
Reactant: Cc1nc2cc(C(=O)O)ccc2[nH]1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: N
Product: Cc1nc2cc(C(=O)NC3C4CC5CC3CN(C5)C4)ccc2[nH]1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 2-methyl-1H-benzimidazole-5-carboxylic acid (Acros) according to methods A and C; yield 84 mg, 0.21 mmol (58%): 1H NMR (300 MHz, methanol-d4) δ 1.99 (d, J=13 Hz, 2 H), 2.30-2.46 (m, 3H), 2.51 (s, 2H), 2.90 (s, 3H), 3.59 (s, 2H), 3.69 (s, 4H), 4.45 (s, 1 H), 7.82 (dd, J=9, 1 Hz, 1H), 8.07 (dd, J=8, 1 Hz, 1H), 8.25 (dd, J=1, 1 Hz, 1H), 8.50 (d, J=5 Hz, 1H); MS (DCI/NH3) m/z 311 (M+H)+; Anal. C18H22N4O.2HCl.1.0H2O: C, H, N.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(C)(C)C.[CH2:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH:20]1[CH2:28]O>>[CH2:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH:20]1[CH2:28][O:16][C:13]1[CH:12]=[CH:11][C:10]([C:9]([NH:8][CH2:7][C:6]([OH:5])=[O:18])=[O:17])=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc(O)cc1
Reactant: OCC1Cc2ccccc2C1
Product: O=C(O)CNC(=O)c1ccc(OCC2Cc3ccccc3C2)cc1
Yield: 85 %

Procedure:
The same reaction as in Example 1 (1b) was conducted using N-(4-hydroxybenzoyl)glycine tert-butyl ester (250 mg, 0.995 mmol) prepared in Example 1 (1a) and 2,3-dihydro-1H-inden-2-ylmethanol (which is the compound disclosed in J. Med. Chem., (1989), 32, 1326-1334, 165 mg, 1.11 mmol) to give 263 mg of the title compound (colorless crystalline solid, yield: 85%).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[N:8][C:9]([N:12]3[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]3)=[N:10][CH:11]=2)=[N:4][N:3]=[N:2]1.C(N(CC)CC)C.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1COCC1>[OH:18][CH:15]1[CH2:14][CH2:13][N:12]([C:9]2[N:8]=[CH:7][C:6]([C:5]3[N:4]=[N:3][N:2]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:1]=3)=[CH:11][N:10]=2)[CH2:17][CH2:16]1
Reactant: CCOC(=O)CBr
Reactant: OC1CCN(c2ncc(-c3nnn[nH]3)cn2)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)Cn1nnc(-c2cnc(N3CCC(O)CC3)nc2)n1
Temperature: 80 °C

Procedure:
A mixture of 1-[5-(1H-tetrazol-5-yl)pyrimidin-2-yl]piperidin-4-ol (550 mg, 2.224 mmol), triethylamine (0.62 mL, 4.45 mmol), ethyl bromoacetate (371 μL, 3.34 mmol) in THF (77.4 mL) was heated at 80° C. for 1 h. The solvent was evaporated, diluted with water (5 mL) and slurried with Et2O (5 mL). The mixture was filtered and washed with water followed by Et2O. The solid was dried under high vacuum to afford the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[S:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[C:4](=[O:15])[NH:3]1.[H-].[Na+].[CH3:18][O:19][CH2:20]Br>CN(C=O)C.C(Cl)Cl>[CH3:1][N:2]1[C:6](=[S:7])[N:5]([C:8]2[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)[C:4](=[O:15])[N:3]1[CH2:18][O:19][CH3:20]
Reactant: Cn1[nH]c(=O)n(-c2ccc(Cl)cc2)c1=S
Reactant: COCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCn1c(=O)n(-c2ccc(Cl)cc2)c(=S)n1C
Reaction time: 0.5 h

Procedure:
To 1-methyl-4-(4-chlorophenyl)-1,2,4-triazolidin-3-one-5-thione (5 g) in 200 ml dry DMF was added 0.91 g sodium hydride. After stirring for 30 minutes, bromomethyl methyl ether (2.63 g) was added dropwise, then heated to reflux for 30 minutes, and stirred overnight at room temperature. The solvent was stripped and the residue was dissolved in methylene chloride, washed with water, and chromatographed on a silica gel column (200 g) by elution with methylene chloride, followed by 2.5% methanol in methylene chloride. Yield: 4.8 g.
Reaction SMILES: [C:1]([O:5][C:6]([C@:8]1([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:13][C@@H:12](Br)[C@@H:11]2[C@H:9]1[C@H:10]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:30]1[CH:34]=[N:33][C:32]([SH:35])=[N:31]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([C@:8]1([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:13][C@H:12]([S:35][C:32]2[N:33]=[CH:34][NH:30][N:31]=2)[C@@H:11]2[C@H:9]1[C@H:10]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Sc1nc[nH]n1
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)C[C@@H](Br)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)C[C@H](Sc2nc[nH]n2)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Temperature: 80 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
Add to a solution of ditert-butyl(1R,2S,4R,5R,6R)-4-bromo-2-(tert-butoxycarbonylamino)bicyclo[3.1.0]hexane-2,6-dicarboxylate (2 g, 4.20 mmol) in dimethylformamide (10 mL), 1H-1,2,4-triazole-3-thiol (525 mg, 5.04 mmol) and potassium carbonate (1.16 g, 8.4 mmol). Stir the mixture at 80° C. overnight. Cool to room temperature and dilute with ethyl acetate, wash with 10% citric acid and brine, dry over anhydrous sodium sulfate, filter and concentrate to dryness. Purify by silica gel chromatography (80 g silica column) eluting with hexane:ethyl acetate (80:20 to 0:100) to obtain the title compound (1.64 g, 78%). MS (m/z): 497 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][CH:11]2[O:15][C:14]([NH2:16])=[N:13][CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:19](OCC)(=[O:22])[CH:20]=[CH2:21]>C(O)C>[C:1]([C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][CH:11]2[O:15][C:14]3=[N:16][C:19](=[O:22])[CH2:20][CH2:21][N:13]3[CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC(=O)OCC
Reactant: CC(C)(C)c1ccc(OCC2CN=C(N)O2)cc1
Solvent: CCO
Product: CC(C)(C)c1ccc(OCC2CN3CCC(=O)N=C3O2)cc1
Temperature: 130 °C
Reaction time: 0.17 h
Yield: 30.7 %

Procedure:
To a solution of 5-(4-tert-butyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (520 mg, 2.10 mmol) in ethanol (10 mL) was added ethyl acrylate (273.3 mg, 2.73 mmol). The reaction mixture was heated in a microwave oven at 130° C. for 10 min, then at 140° C. for 10 min, and finally at 150° C. for 30 min. Solvent was removed under vacuum, and the residual solid washed with small amount of EtOH to afford 195 mg of 2-(4-tert-butyl-phenoxymethyl)-2,3,5,6-tetrahydro-oxazolo[3,2-a]pyrimidin-7-one as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:27]C)[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([S:18][C:19]3[S:23][C:22]([NH2:24])=[CH:21][CH:20]=3)=[CH:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:25][CH3:26])C.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=1>O1CCCC1>[CH3:27][N:3]([CH3:1])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([S:18][C:19]3[S:23][C:22]([NH:24][C:37]([NH:36][C:33]4[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=4)=[O:38])=[CH:21][CH:20]=3)=[CH:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:25][CH3:26]
Reactant: CCN(CC)CCCOc1cc2nccc(Sc3ccc(N)s3)c2cc1OC
Reactant: O=C=Nc1ccc(F)cc1
Solvent: C1CCOC1
Product: COc1cc2c(Sc3ccc(NC(=O)Nc4ccc(F)cc4)s3)ccnc2cc1OCCCN(C)C
Yield: 6.7 %

Procedure:
5-({7-[3-(Diethylamino)propoxy]-6-methoxy-4-quinolyl}sulfanyl)-2-thiophenylamine (190 mg), parafluorophenyl isocyanate (69 mg) and tetrahydrofuran (30 ml) were stirred together at room temperature for 30 minutes. The organic solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (ethyl acetate, followed by ethyl acetate:methanol=10:1) using NH type silica gel. The solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue for solidification to obtain 16 mg of a yellowish-brown solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)=[N:10][N:11]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH3:31][NH2:32]>O.O1CCOCC1>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:11]2[CH:12]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:32][CH3:31])[CH:7]=3)[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)=[N:10]2)=[CH:15][CH:16]=1
Reactant: CN
Reactant: COc1ccc(Cn2cc(-c3ccnc(F)c3)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Solvent: C1COCCO1
Solvent: O
Product: CNc1cc(-c2cn(Cc3ccc(OC)cc3)nc2-c2cccc([N+](=O)[O-])c2)ccn1
Yield: 58 %

Procedure:
500 mg (1.24 mmol) of 2-fluoro-4-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]pyridine were dissolved in a mixture of 6 ml of methylamine 40% in water and 12 ml of dioxane and the mixture submitted to microwave irradiation at 130° C. for 2 hours in a sealed vial. The solvent was the removed under reduced pressure and the residue taken up with dichloromethane and washed with water. The organic layer was dried over sodium sulphate and evaporated. The crude was finally purified by flash-chromatography on a silica gel column (CH2Cl2-CH3COCH3 9/1), giving 300 mg (58%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[F:10][C:11]([Si](C)(C)C)([F:13])[F:12].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]([OH:6])[C:11]([F:13])([F:12])[F:10])[CH:3]=1
Reactant: O=Cc1cccc(F)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1cccc(F)c1)C(F)(F)F
Yield: 120.4 %

Procedure:
According to Reference Example 8-12, by use of 3-fluorobenzaldehyde (500 mg, 4.03 mmol), (trifluoromethyl)trimethylsilane (715 μL, 4.83 mmol), tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 403 μL, 0.403 mmol) and tetrahydrofuran (10 mL), the mixture was stirred and reacted at room temperature for 3 hours. Thus, 1-fluoro-3-(2,2,2-trifluoro-1-hydroxyethyl)benzene (Compound DA) (942 mg, yield: quantitative) was obtained.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[C:2]=[O:3].[NH:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[N:15]1>C(Cl)Cl>[C:8]1([CH2:7][CH2:6][CH2:5][CH2:4][NH:1][C:2]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[N:15]2)=[O:3])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc2[nH]nnc2c1
Reactant: O=C=NCCCCc1ccccc1
Solvent: ClCCl
Product: O=C(NCCCCc1ccccc1)n1nnc2ccccc21
Temperature: 22.5 °C
Reaction time: 8 h

Procedure:
(4-Isocyanatobutyl)benzene (463 mg, 2.64 mmol) was added dropwise to a stirred solution of 1H-benzo[d][1,2,3]triazole (300 mg, 2.52 mmol) in DCM (18 ml) at 0-5° C. The clear reaction mixture was allowed to stir at 20-25° C. overnight. The solvent was removed in vacuum to give a clear oil. The oil solidified on standing into a colourless solid. The product was recrystallised from 2-propanol, the solid was collected, dried in vacuum at 45° C. Yield 477 mg (64%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([C:12]2[N:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]3)=[CH:36][CH:35]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(-c3ccccc3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: COc1ccc(-c2c3c(nn2-c2ccccc2)CCNCC3)cc1
Yield: 31.8 %

Procedure:
The title compound (43.6 mg) was prepared from 198.3 mg of 2-phenyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 176, Step B) and 94.7 mg of 4-methoxyphenylboronic acid as described in Example 199. MS (ESI): exact mass calculated for C20H21N3O, 319.17; found, m/z 320.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.28-7.24 (m, 2H), 7.21-7.17 (m, 3H), 7.07 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 3.81 (s, 3H), 3.11-3.08 (m, 2H), 3.04-3.01 (m, 2H), 3.00-2.97 (m, 2H), 2.68-2.65 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:9]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[C:10]=2[F:17])=[CH:6][N:5]=[C:4]([C:31]([NH2:33])=[O:32])[CH:3]=1.C=O.[OH-].[Na+].[C:38](OCC)(=[O:40])C>COCCOC>[OH:40][CH2:38][NH:33][C:31]([C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([CH:8]([S:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=2)(=[O:20])=[O:19])[C:9]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[C:10]=2[F:17])=[CH:6][N:5]=1)=[O:32]
Reactant: Cc1cc(C(N)=O)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(C)=O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: Cc1cc(C(=O)NCO)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 15 h
Yield: 77 %

Procedure:
To a solution of 4-methyl-5-[[[4-(trifluoromethyl)phenyl]sulfonyl](2,3,6-trifluorophenyl) methyl]pyridine-2-carboxamide (171 mg, 0.350 mmol) in ethylene glycol dimethyl ether (5 ml), an aqueous solution of formaldehyde (37%, 78.9 μl) and an aqueous sodium hydroxide (17.5 μl) were added at room temperature, and the mixture was stirred for 15 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous ammonium chloride. Subsequently, 1 N hydrochloric acid was added to the organic layer, and the mixture was stirred for 1 hour. After the organic layer was separated, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was subjected to flash silica gel chromatography, and the fraction obtained from an elution with hexane:ethyl acetate=1:1 was concentrated under reduced pressure. The resulting residue was washed with a mixed solvent of 2-propanol and hexane, and then was collected by filtration, to obtain the title compound (139 mg, 0.268 mmol, 77%) as a white solid.