Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]([CH:9]([CH3:11])[CH3:10])[NH2:8])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[Cl:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([S:31](Cl)(=[O:33])=[O:32])[CH:29]=2)[C:24]([Cl:35])=[CH:23][N:22]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:12])[C@@H:7]([CH:9]([CH3:10])[CH3:11])[NH:8][S:31]([C:28]1[CH:29]=[C:30]2[C:25]([C:24]([Cl:35])=[CH:23][N:22]=[C:21]2[Cl:20])=[CH:26][CH:27]=1)(=[O:33])=[O:32])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[C@@H](N)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc2c(Cl)cnc(Cl)c2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@@H](NS(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1)C(=O)OC(C)(C)C
Temperature: 23 °C
Reaction time: 16 h
Yield: 72.2 %

Procedure:
D-Valine t-butyl ester (354 mg, 1.69 mmol) and then NEt3 (0.59 mL, 4.2 mmol) were added to a stirred solution of 1,4-dichloro-7-isoquinolinesulphonyl chloride (500 mg, 1.69 mmol) and in CH2Cl2 (20 mL) and the mixture was stirred at 23° C. for 16 h. The mixture was diluted with CH2Cl2 (50 mL), washed with saturated aqueous NaHCO3, water, aqueous citric acid (1 M), water, brine, dried (MgSO4) and evaporated in vacuo. The residue was dissolved in i-Pr2O and hexane was added which gave a precipitate. The solvents were evaporated in vacuo and the solid was triturated with hexane to give N-[(1,4-dichloro-7-isoquinolinyl)sulphonyl]-D-valine t-butyl ester (532 mg, 1.22 mmol) as a white solid. An analytical sample was obtained by recrystallisation from hexane.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]([C:12]([NH2:14])=O)=[CH:5][C:4]=2[N:3]1[CH2:15][CH:16]=[CH2:17].C(N(CC)CC)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]([C:12]#[N:14])=[CH:5][C:4]=2[N:3]1[CH2:15][CH:16]=[CH2:17]
Reactant: C=CCn1c(=O)ccc2ncc(C(N)=O)cc21
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCn1c(=O)ccc2ncc(C#N)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a suspension of 6-oxo-5-(2-propen-1-yl)-5,6-dihydro-1,5-naphthyridine-3-carboxamide (0.69 g, 3 mmol) in DCM (30 ml) at 0° C. was added triethylamine (1.0 ml, 7.2 mmol) and trifluoromethanesulfonic anhydride (0.605 ml, 3.6 mmol) and the reaction was allowed warm to rt and stirred for 1 h at rt. Another four sequential treatments of triethylamine (1.0 ml, 7.2 mmol) and trifluoromethanesulfonic anhydride (0.605 ml, 3.6 mmol) over the next 6 h were necessary to drive the reaction almost to completion. The reaction mixture was treated with sat. aq NaHCO3 and the aqueous extracted twice more with DCM. The combined organic phases were then dried, evaporated and the residue was subjected to column chromatography on silica gel using a EtOAc:hexane gradient to provide the desired compound (0.570 g, 90%).
Reaction SMILES: C[N:2]([CH3:20])/[CH:3]=[C:4](/[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([I:17])[CH:14]=[CH:13][C:12]=1F)\[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:21][O:22][CH2:23]CN.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[I:17][C:15]1[CH:16]=[C:11]2[C:12](=[CH:13][CH:14]=1)[N:2]([CH2:20][CH2:21][O:22][CH3:23])[CH:3]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]2=[O:19]
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1cc(I)ccc1F
Reactant: COCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CCOC)c2ccc(I)cc2c1=O
Temperature: 90 °C
Yield: 63.3 %

Procedure:
(Z)-Ethyl 3-(dimethylamino)-2-(2-fluoro-5-iodobenzoyl)acrylate (0.428 g, 1.09 mmol, Intermediate 24) and 2-methoxyethanamine (0.082 g, 1.09 mmol, Acros) were combined in DMF (3.0 mL). Potassium carbonate (0.151 g, 1.09 mmol, Fisher) was added and the reaction was heated in the microwave at 90° C. for 30 min After 30 minutes, LC/MS indicated that the reaction was complete. The reaction mixture was cooled to room temperature and slowly poured into water. The resulting precipitate was filtered, washed with water and dried overnight to yield a white solid (0.277 g).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5](=[O:9])[CH:6]([CH3:8])[CH3:7].[CH:13]([O-])([O-])[O:14][CH2:15][CH3:16].C(OC(=O)C)(=O)C>>[CH2:15]([O:14][CH:13]=[C:4]([C:5](=[O:9])[CH:6]([CH3:8])[CH3:7])[C:3](=[O:10])[C:2]([F:11])([F:12])[F:1])[CH3:16]
Reactant: CC(C)C(=O)CC(=O)C(F)(F)F
Reactant: CCOC([O-])[O-]
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)C(C)C)C(=O)C(F)(F)F
Yield: 52.4 %

Procedure:
A mixture comprising 213 g (1.17 mol) of 1,1,1-trifluoro-5-methyl-2,4-hexanedione, 242 g (1.64 mol) of ethyl orthoformate and 166 g (1.63 mol) of acetic anhydride, was heated and refluxed for 6 hours. The solvent was distilled off under reduced pressure to obtain 146 g (yield: 67%) of 3-ethoxymethylene-1,1,1-trifluoro-5-methyl-2,4-hexanedione.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][OH:11])[CH3:8])[CH3:3].[Cr]([O-])([O-])(=O)=[O:13].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>>[C:10]([OH:13])(=[O:11])[CH2:9][CH:7]([CH2:6][CH2:5][CH:4]=[C:2]([CH3:3])[CH3:1])[CH3:8]
Reactant: CC(C)=CCCC(C)CCO
Reactant: O=[Cr](=O)([O-])[O-]
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CC(C)=CCCC(C)CC(=O)O

Procedure:
Citronellol is oxidized with a chromate-type oxidizing agent (e.g., Jones reagent) to the carboxylic acid which is then esterified to give an ester of citronellic acid. The double bond is converted into an epoxide by a peroxide as described in Step 4. And then, the epoxide is oxidatively cleaved with a periodate to give an aldehyde, which is converted into the olefinic compound by convention Wittig reaction using trimethylphosphonium bromide and a base. The compound thus prepared is condensed with dimethyl methylphosphonate in the presence of base to give the desired compound. When an optically active compound such as (S)-(-)-citronellol is used as a starting material and allowed to react in the same manner, (S)-dimethyl 2-oxo-4-methyl-7-octenylphosphonate is prepared.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:25])[C:4](=[O:24])[C:5]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]([F:23])[F:22])=[CH:16][CH:15]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=2)[N:6]=1.[CH2:26](O)[CH2:27][CH:28]=[CH2:29].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[NH2:1][C:2]1[N:3]([CH3:25])[C:4](=[O:24])[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:29][CH2:28][CH:27]=[CH2:26])[CH:8]=2)([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]([F:22])[F:23])=[CH:16][CH:15]=2)[N:6]=1
Reactant: C=CCCO
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2cccc(O)c2)N=C1N
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCCOc1cccc(C2(c3ccc(OC(F)F)cc3)N=C(N)N(C)C2=O)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 63.5 %

Procedure:
To a solution of 2-amino-4-(4-(difluoromethoxy)phenyl)-4-(3-hydroxyphenyl)-1-methyl-1H-imidazol-5(4H)-one (0.070 g, 0.20 mmol), but-3-en-1-ol (0.023 g, 0.32 mmol), and PS—PPh3 (0.145 g, 0.32 mmol, 2.2 mmol/g) in THF (2 mL) is added diethylazodicarboxylate (0.058 g, 0.38 mmol) in THF (0.5 mL) dropwise. The mixture is stirred at 60° C. for 4 h. The solution is cooled to RT and the PPh3 is filtered and washed with CH2Cl2 and MeOH. The solvent is removed, the remaining material is absorbed onto Celite and purified by Flash Chromatography (15:1 CH2CL2:MeOH) to yield 2-amino-4-(3-(but-3-enyloxy)phenyl)-4-(4-(difluoromethoxy)phenyl)-1-methyl-1H-imidazol-5(4H)-one (0.051 g, 73%) as an off white foam.
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[CH:18])(C)(C)C.C([C:22]1[CH:27]=[C:26]([S:28]([CH2:31][CH2:32]C)(=[O:30])=[O:29])[CH:25]=[CH:24][C:23]=1[CH3:34])#C>>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:19])=[C:10]([C:17]#[C:18][C:24]2[CH:25]=[C:26]([S:28]([CH2:31][CH3:32])(=[O:29])=[O:30])[CH:27]=[CH:22][C:23]=2[CH3:34])[CH:11]=1)#[N:16]
Reactant: C#Cc1cc(S(=O)(=O)CCC)ccc1C
Reactant: C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C
Product: CCS(=O)(=O)c1ccc(C)c(C#Cc2cc(C#N)ccc2OCC(=O)O)c1

Procedure:
Following the general method as outlined in Example 37, starting from tert-butyl(4-cyano-2-ethynyl phenoxy)acetate (Intermediate 46) and 2-ethynyl-1-methyl-4-(propylsulfonyl)benzene (Intermediate 40), the title compound was obtained as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH3:11])[C:3]1=[S:12].[Cl:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:13][C:4]1([CH3:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[C:3]1=[S:12]
Reactant: CC1C(=S)N(C)c2ccccc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CN1C(=S)C(C)(Cl)c2ccccc21

Procedure:
A solution of 1-methyl-3-methylthiooxindole (1.07 g, 5.56 mmol) and N-chlorosuccinimide (800 mg, 6.0 mmol) in 75 ml of carbon tetrachloride was stirred at room temperature for 1 hour, filtered, and the filtrate was evaporated to give a residue yielding 3-chloro-1-methyl-3-methylthiooxindole. The residue was dissolved in 20 ml of tetrahydrofuran and rapidly added to a vigorously stirred slurry of red mercuric oxide (1.20 g, 5.56 mmol) and boron trifluoride etherate (790 mg, 5.56 mmol) in 75 mol of 20 percent aqueous tetrahydrofuran. After stirring at room temperature for 1 hour, the reaction mixture was filtered through a Celite pad and the filtrate was extracted with ether. Evaporation of the ether layer gave a residue which was purified by chromatography on silica gel. Elution with methylene chloride gave 1-methylisatin (550 mg, 61%), mp 131°-133°; nmr (CDCl3) τ2.23-2.60 (m, 2H, aromatic H), 2.71-2.90 (m, 2H, aromatic H) and 6.70 (s, 3H, N--CH3).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9](Br)[CH2:10][OH:11].C([O-])([O-])=O.[K+].[K+].CC(C)=O>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1
Reactant: OCCBr
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: OCCOc1ccc(Br)cc1
Yield: 44.2 %

Procedure:
In a reactor, 10.0 g of 4-bromophenol, 7.95 g of ethylene bromohydrin, 16.0 g of K2CO3, and 300 ml of acetone were charged, and stirred and refluxed for 50 hours to give a reaction solution. The reaction solution was poured into water, extracted with toluene, washed with water, and thereafter dried over sodium sulfate anhydride, and the solvent was evaporated and the residue was distilled under reduced pressure in GTO (glass tube oven) to give 5.55 g (Y., 44.3%) of 1-bromo-4-(2-hydroxyethoxy) benzene.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.Cl.[NH2:30][C:31]1([CH2:34][OH:35])[CH2:33][CH2:32]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[OH:35][CH2:34][C:31]1([NH:30][C:23](=[O:24])[C:22]2[CH:21]=[CH:20][C:19]([CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[CH2:10][C:9]([C:4]3[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=3)=[O:28])=[CH:27][CH:26]=2)[CH2:33][CH2:32]1
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Reactant: NC1(CO)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NC2(CO)CC2)cc1

Procedure:
In analogy to example 207, step 2, 4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (example 207, step 1) was coupled with (1-aminocyclopropyl)methanol hydrochloride using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as an off-white solid, MS (ESI+): m/z=445.4 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].C1(C2CC(O)C3C(=CC=C(O)C=3)[O:34]2)C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:15][CH:14]3[OH:34])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Oc1ccc2c(c1)C(O)CC(c1ccccc1)O2
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)C(O)CC(c2ccccc2)O3)nc1

Procedure:
6-(5-Nitropyridin-2-yloxy)-2-phenylchroman-4-ol was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1 (b) starting from 1.5 g of 2-phenylchroman-4,6-diol. The product was passed through a silica gel column using toluene-ethyl acetate (4:1) as an eluant and then crystallised from 2-propanol. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.7 Hz), 8.61 (dd, 1H, J 9.1, 2.7 Hz), 7.50-7.36 (m, 5H), 7.25 (d, 1H, J 2.7 Hz), 7.22 (d, 1H, 9.1 Hz), 7.00 (dd, 1H, J 8.7, 2.7 Hz), 6.88 (d, 1H, J 8.7 Hz), 5.65 (d, 1H, J 6.3 Hz), 5.30 (dd, 1H, J 11.9, 1.3 Hz), 4.99 (m, 1H), 2.33 (m, 1H), 1.98 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[C:21]([C:22]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:23]=2[CH2:24][CH2:25][NH:26][CH:27]3[CH3:32])=[CH:20][CH:19]=[CH:18][N:17]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][CH:30]=[CH:31][C:22]=4[C:21]4[C:16]([O:15][CH3:14])=[N:17][CH:18]=[CH:19][CH:20]=4)[CH:27]3[CH3:32])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: COc1ncccc1-c1cccc2c1CCNC2C
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: COc1ncccc1-c1cccc2c1CCN(C(=O)c1cc3ncc(Cl)cn3n1)C2C

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-(2-Methoxy-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9][CH2:8]1)=[O:6].[O:18]([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][CH2:4][C:5]([N:7]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[O:11][CH2:10][CH2:9][CH2:8]3)=[O:6])[CH2:33][CH2:32]2)=[CH:27][CH:26]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(CCCCl)N1CCCOc2ccccc21
Reactant: c1ccc(Oc2ccc(N3CCNCC3)cc2)cc1
Product: O=C(CCCN1CCN(c2ccc(Oc3ccccc3)cc2)CC1)N1CCCOc2ccccc21

Procedure:
The compound (16) synthesized in Reference Example 16 and 1-(4-phenoxylphenyl)piperazine [DE 2631885] were used to produce the above compound in the same way as Example 1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[Br:35][C:36]1[CH:37]=[C:38]([C:43]([F:46])([F:45])[F:44])[C:39](O)=[N:40][CH:41]=1.C(P(CCCC)CCCC)CCC.C(OC(C)C)(C)C>C1(C)C=CC=CC=1>[Br:35][C:36]1[CH:37]=[C:38]([C:43]([F:46])([F:44])[F:45])[C:39]([O:1][CH2:2][CH2:3][CH:4]2[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]2)=[N:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: Oc1ncc(Br)cc1C(F)(F)F
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CC(C)OC(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ncc(Br)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
tert-Butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (7.7 g) and 1,1′-(azodicarbonyl)dipiperidine (11.6 g) were added to a mixture of 5-bromo-3-(trifluoromethyl)pyridine-2-ol (7 g) and toluene (124 mL) at room temperature. Tributylphosphine (11.6 mL) was added thereto under ice-cooling, and the mixture was stirred at room temperature overnight. After diisopropylether was added to the reaction mixture, the mixture was stirred, and the insoluble material was separated by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Hex:EtOAc=100:0 to 70:30), whereby tert-butyl 4-(2-{[5-bromo-3-(trifluoromethyl)pyridin-2-yl]oxy}ethyl)piperidine-1-carboxylate (8.93 g) was obtained as a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5](=[O:9])[O:6][C:7]=1[CH3:8].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][CH2:2][C:3]2[O:4][C:5](=[O:9])[O:6][C:7]=2[CH3:8])=[CH:13][CH:12]=1
Reactant: Cc1oc(=O)oc1CCl
Reactant: Sc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1oc(=O)oc1CSc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
In 40 ml of dichloromethane was dissolved 2.0 g of 4-chloromethyl-5-methyl-1,3-dioxol-2-one, and 2.0 g of 4-chlorobenzenethiol was added. Then, 1.4 g of triethylamine was added, and the mixture was stirred at room temperature for 30 minutes. After the reaction, the solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The insoluble materials were separated by filtration, and the solvent was evaporated under reduced pressure. The residue was subjected to medium-pressure silica gel column chromatography as in Example 1. The eluate was evaporated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate and n-hexane to give 2.9 g of the captioned compound as colorless crystals.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[S:5][CH2:4][C:2]1=[O:3].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[C:27](O)(=[O:41])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]/[CH:35]=[CH:36]\[CH2:37][CH2:38][CH2:39][CH3:40].Cl>CN(C)C=O.CN(C)C1C=CN=CC=1>[OH:3][C:2]1[CH2:4][S:5][C:6](=[O:7])[C:1]=1[C:27](=[O:41])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]/[CH:35]=[CH:36]\[CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCC/C=C\CCCCCCCC(=O)O
Reactant: O=C1CSC(=O)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCC/C=C\CCCCCCCC(=O)C1=C(O)CSC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.8 %

Procedure:
To a stirring solution of 855 mg (7.37 mmol) of thiotetronic acid in 10 mL of dimethylformamide is added 902 μL (6.47 mmol) of triethylamine and 240 mg (1.96 mmol) of 4-dimethylaminopyridine at 0° C. Next, 1.68 g (8.76 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 2.0 g (8.84 mmol) of myristoleic acid are added and the reaction mixture is stirred overnight at room temperature. The reaction is acidified with 1.0 N HCl and extracted three times with diethyl ether. The combined organic layers are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue is subjected to HPLC chromatography (2 inch Dynamax silica gel column, 25 mL/min) eluting with 100% ethyl acetate to give 785 mg (33%) of 4-hydroxy-3-[(Z)-1-oxo-9-tetradecenyl]-2(5H)-thiophenone as an oil.
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=[O:4])=[O:3].O[CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:5][CH:15]1[CH2:16][CH2:11][CH2:12][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(OS(C)(=O)=O)C1
Reaction time: 1 h

Procedure:
Methanesulfonic anhydride (996 mg, 5.72 mmol) was added to a mixture of 3-hydroxy-N-t-butoxycarbonylpiperidine (959 mg, 4.76 mmol) and triethylamine (0.86 ml, 6.19 mmol) in methylene chloride (30 ml) at 0° C. After stirring for 1 h, the reaction mixture was washed with saturated NaHCO3 and dried (Na2SO4). Concentration gave the title compound. 1H NMR (CDCl3) d 1.46 (s, 9 H), 1.77-2.17 (m, 4 H), 3.05 (s, 3 H), 3.14-3.49 (m, 2 H), 3.62 (m, 2 H), 4.72 (br s, 1 H).
Reaction SMILES: [ClH:1].Cl.[NH:3]1[CH:7]=[C:6]([CH2:8][N:9]2[C:15]3[CH:16]=[C:17]([NH2:20])[CH:18]=[CH:19][C:14]=3[CH2:13][N:12]([C:21]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)=[O:22])[CH2:11][CH2:10]2)[N:5]=[CH:4]1.[CH3:33][N:34]1[CH2:42][CH2:41][CH2:40][CH2:39][CH:35]1[C:36](O)=[O:37]>>[ClH:1].[ClH:1].[ClH:1].[CH3:33][N:34]1[CH2:42][CH2:41][CH2:40][CH2:39][CH:35]1[C:36]([NH:20][C:17]1[CH:18]=[CH:19][C:14]2[CH2:13][N:12]([C:21]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)=[O:22])[CH2:11][CH2:10][N:9]([CH2:8][C:6]3[N:5]=[CH:4][NH:3][CH:7]=3)[C:15]=2[CH:16]=1)=[O:37]
Reactant: CN1CCCCC1C(=O)O
Reactant: Nc1ccc2c(c1)N(Cc1c[nH]cn1)CCN(C(=O)c1cccc3ccccc13)C2
Agent: Cl
Product: CN1CCCCC1C(=O)Nc1ccc2c(c1)N(Cc1c[nH]cn1)CCN(C(=O)c1cccc3ccccc13)C2

Procedure:
Example 90 was prepared as a light yellow solid from Example 26 and N-methyl-pipecolic acid as described for Example 62.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[N:6]([CH2:17][C:18]#[N:19])[C:5]=2[CH:4]=[N:3]1.[OH-:20].[K+].O>CC(O)(C)C>[CH3:1][N:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[N:6]([CH2:17][C:18]([NH2:19])=[O:20])[C:5]=2[CH:4]=[N:3]1
Reactant: [OH-]
Reactant: Cc1ccc2c(c1)c(=O)c1c(cnn1C)n2CC#N
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1ccc2c(c1)c(=O)c1c(cnn1C)n2CC(N)=O
Temperature: 85 °C
Reaction time: 0.17 h
Yield: 58.9 %

Procedure:
To a solution warmed at 85° C. of (1,7-dimethyl-9-oxo-1,9-dihydro-4H-pyrazolo[4,3-b]quinolin-4-yl)acetonitrile (EXAMPLE 51, 69 mg, 0.27 mmol) in 2-methyl-2-propanol (5 ml) was added powdered potassium hydroxide (76 mg, 1.4 mmol). The mixture was stirred at 85° C. for 10 min. After cooling to ca. 40° C., the mixture was poured into water (30 ml) and extracted with ethyl acetate (30 ml×3). The combined organic layer was washed with brine (50 ml), dried over magnesium sulfate, and concentrated in vacuo. The residue was washed with diisopropyl ether and ethyl acetate to give 43 mg (59%) of the title compound as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]([OH:15])=O.C(Cl)(=O)C([Cl:19])=O>ClCCl.CN(C=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]([Cl:19])=[O:15]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CN1C(=O)c2ccccc2C1=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CN1C(=O)c2ccccc2C1=O

Procedure:
To 10.25 g of (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetic acid dissolved in 50 ml of dichloromethane are added, at room temperature, 4.6 ml of oxalyl chloride and 2 drops of DMF, and the mixture is left for 18 hours at room temperature. The resulting mixture is evaporated to dryness to give 11 g of the expected product.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:12]([OH:14])=O.C(N(CC)CC)C.ClC(OCC)=O.[CH3:28][NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>ClCCl>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:12]([N:29]([CH3:28])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)=[O:14]
Reactant: O=C(O)c1nnc2ccccc2c1O
Reactant: CNc1ccccn1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)c1nnc2ccccc2c1O)c1ccccn1
Reaction time: 1 h
Yield: 14 %

Procedure:
4-Hydroxy-cinnoline-3-carboxylic acid (8.8 g) is dissolved in dichloromethane (600 ml) in the presence of triethylamine (5.6 g). To this solution ethyl chloroformate (6 g) diluted with dichloromethane (50 ml) is added dropwise under stirring at a temperature varying between 0° C. and about 5° C. The mixture is allowed to react at 0°-5° C. for 1 hour, then 2-methylamino-pyridine (4.55 g) is added. The reaction mixture is kept at 0°-5° C. for 1 hour, then at room temperature for 2 hours, under stirring. The organic solution is washed with 2.5% NaHCO3 and water, then is evaporated to dryness in vacuo. The residue is purified over a SiO2 column using ethyl acetate, then ethylacetate-methanol=95:5 as eluents. Crystallization from ethanol yields 1.65 g of 4-hydroxy-N-methyl-N-(2-pyridyl)-cinnoline-3-carboxamide, m.p. 237°-239° C., NMR (DMSO d6) δ ppm: 3.43 (s) (3H, CH3), 7.0-8.3 (m) (8H, phenyl and pyridyl protons).