Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH2:15])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:4][CH2:3][CH2:2]1.N1CCOCC1.[N+:22]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1)([O-:24])=[O:23]>C1(C)C=CC=CC=1>[N+:22]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[N:15][C:13]2[C:12]3[C:7]([N:6]=[C:5]4[C:14]=2[CH2:1][CH2:2][CH2:3][CH2:4]4)=[CH:8][CH:9]=[CH:10][CH:11]=3)=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: Nc1c2c(nc3ccccc13)CCCC2
Solvent: C1COCCN1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(C=Nc2c3c(nc4ccccc24)CCCC3)cc1
Yield: 50.6 %

Procedure:
1,2,3,4-Tetrahydro-9-acridinamine (4.0 g) was refluxed in 400 ml of toluene containing morpholine (3.5 g) and 4-nitrobenzaldehyde (3.78 g). After forty-eight (48) hours an additional 3.78 g of aldehyde was added and reflux was continued for an additional twenty-four (24) hours. At the end of this time the reaction mixture was concentrated and purified by flash chromatography. Fractions containing the product were concentrated and recrystallized from CH2Cl2 /pentane to give 3.38 g of product, m.p. 237°-238° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:7]=1.[NH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:14])(=[O:13])[NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[CH:7]=1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1cccc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)C=Cc1cccc(S(=O)(=O)Nc2cccc3ccccc23)c1
Yield: 51.6 %

Procedure:
A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (3) (0.4 g, 1.53 mmol) in dioxane (5 ml) was added to a mixture of 1-aminonaphthalene (0.22 g, 1.53 mmol) in dioxane (1 ml) and NaHCO3 (0.26 g, 3.09 mmol) in water (3 ml), and the resultant solution was stirred at room temperature until the completion of the reaction (control by TLC). The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with petroleum ether-ethyl acetate (gradient from 2:1 to 1:1, v/v) as eluent. The obtained product was washed with diethyl ether to give the title compound (0.29 g, 51%) as a white solid. 1H NMR (DMSO-d6, HMDSO), δ: 3.69 (3H, s); 6.56 (1H, d, J=16.0 Hz); 7.16 (1H, dd, J=7.0 and 1.4 Hz); 7.27-8.14 (11H, m); 10.25 (1H, s).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][NH2:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[IH:12].CS[C:15](=[NH:17])[NH2:16]>C(O)C>[IH:12].[C:1]([N:8]([CH2:9][CH2:10][NH2:11])[C:15]([NH2:17])=[NH:16])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CSC(=N)N
Reactant: CC(C)(C)OC(=O)NCCN
Agent: I
Solvent: CCO
Product: CC(C)(C)OC(=O)N(CCN)C(=N)N
Yield: 72.8 %

Procedure:
A solution of commercial N-BOC-ethylendiamine (1 g) in dry ethanol (100 ml) and 2-methyl-2-thiopseudourea hydroiodide (1.5 g) was refluxed for 8 hours. The solvent was removed at reduced pressure and the crude residue purified by flash chromatography (methylene chloride/methanol:9/1) to yield 1.5 g of N-BOC-2-aminoethylguanidine hydroiodide as a yellow oil which was dissolved in methanolic hydrochloric acid solution 5N (20 ml) and stirred at room temperature for 3 hours. The white precipitate was collected and washed with dry ethanol, affording 700 mg of the intermediate.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]([NH:6][C:7](=[O:9])[CH3:8])=[C:4]([F:15])[CH:3]=1.[H][H]>[Pt].C(O)C.O1CCCC1>[NH2:12][C:11]1[C:2]([Cl:1])=[CH:3][C:4]([F:15])=[C:5]([CH:10]=1)[NH:6][C:7](=[O:9])[CH3:8]
Reactant: [H][H]
Reactant: CC(=O)Nc1cc([N+](=O)[O-])c(Cl)cc1F
Agent: [Pt]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(N)c(Cl)cc1F

Procedure:
A mixture of 4'-chloro-2'-fluoro-5'-nitroacetanilide (35.2 g, 151 mmol), and 5% platinum on carbon (7.0 g, 20 wt/wt %) in an ethanol/tetrahydrofuran (2:1) solution is hydrogenated until 28 psi of hydrogen is taken up. The reaction mixture is then filtered, and concentrated in vacuo to give the title product as a tan solid which is identified by 1H NMR spectral analysis.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:8][O:9][C:10]=2[C:11]([F:14])([F:13])[F:12])[N:3]=[CH:2]1.F[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=1>>[C:15]1([C:7]2[C:6]([C:4]3[N:3]=[CH:2][N:1]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=4)[CH:5]=3)=[C:10]([C:11]([F:14])([F:12])[F:13])[O:9][N:8]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: FC(F)(F)c1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: Fc1ccc(C(F)(F)F)cn1
Product: FC(F)(F)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)nc1
Yield: 79 %

Procedure:
As described for Example 4, 4-(1H-imidazol-4-yl)-3-phenyl-5-trifluoromethyl-isoxazole (100 mg, 0.36 mmol) was converted, using 2-fluoro-5-(trifluoromethyl)pyridine instead of 4-fluorobenzotrifluoride, to the title compound (120 mg, 79%) which was obtained as a white solid. MS: m/e=425.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].CS(O[CH:14]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]1)(=O)=O>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH:14]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]1
Reactant: CN1CCC(OS(C)(=O)=O)C1
Reactant: Oc1ccccc1Br
Product: CN1CCC(Oc2ccccc2Br)C1

Procedure:
The title compound was prepared from 2-bromophenol and 1-methylpyrrolidin-3-yl methanesulphonate in a similar manner to Example 134 (b) except that the compound was purified by cation exchange chromatography eluting with ammonia/methanol mixtures.
Reaction SMILES: [NH:1]([C:6]([O:8][CH2:9][CH:10]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7])[CH2:2][C:3]([OH:5])=[O:4].O[C:24]1[C:33]([F:34])=[C:31]([F:32])[C:29]([F:30])=[C:27]([F:28])[C:25]=1[F:26].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[NH:1]([C:6]([O:8][CH2:9][CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]2[C:22]1=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:7])[CH2:2][C:3]([O:5][C:24]1[C:25]([F:26])=[C:27]([F:28])[C:29]([F:30])=[C:31]([F:32])[C:33]=1[F:34])=[O:4]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(CNC(=O)OCC1c2ccccc2-c2ccccc21)Oc1c(F)c(F)c(F)c(F)c1F
Reaction time: 15 h

Procedure:
To a solution of Fmoc-Gly-OH (891 mg, 3.0 mmol) and PfpOH(754 mg, 4.5 mmol) in DMF (12 mL) was added DCC (845 mg, 4.5 mmol) at 0° C. for 30 min and then room temperature for 15 h. The reaction mixture was filterd to remove DCUrea and the flitrate was evaporated in vacuo to give the crude Fmoc-Gly-OPfp. To a solution of Fmoc-Gly-OPfp and BocPNA-OH (436 mg, 2.0 mmol) in DMF (16 mL) was added diisoprppylethylamine (445 il, 2.6 mmol) and the reaction mixture was stirred at room temperature for 15 h. The reaction mixture was evaporated in vacuo and the residue was flush-chromatographed (0-50% MeOH/CH2Cl2) to give Fmoc-Gly-BocPNA-OH (121 mg, 12%). 1H NMR (DMSO-d6) δ 7.88 (d, J=7.0 Hz, 2H), 7.72 (d, J=7.0 Hz, 2H), 7.62 (brt) and 7.56 (brt) (1H), 7.41 (t, J=7.0 Hz, 2H), 7.33 (t, J=7.0 Hz, 2H), 7.18 (m, 2H), 6.85 (brt) and 6.79 (brt) (1H), 4.35-4.15 (m, 3H), 4.05-3.85 (m, 3H), 3.77 (m, 1H), 3.40-3.25 (m, 2H), 3.10 (m) and 3.03 (s) (2H), 1.37 (brs, 9H); 13C NMR (DMSO-d6) δ 172.2 (d), 169.10 (d), 156.34 (d), 155.58 (d), 143.83, 140.66, 127.58, 127.04, 125.24, 120.04, 77.77 (d), 65.71, 47.34 (d), 46.72, 46.65 (d), 29.23 (d), 28.14 (d); FABMS m/z 498 [(M+H)+].
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=C[C:11]=2N=N1.[C:28]([O:32][C:33]([N:35]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[C:36]1[C:45]2[C:40](=[CH:41][C:42]([NH:46][CH:47]([C:51]3[CH:56]=[CH:55][C:54]([C@@H:57]([CH3:79])[CH2:58][O:59][C:60](=[O:78])[NH:61][C:62]4[CH:67]=[C:66]([CH2:68][NH:69][CH3:70])[C:65]([O:71][C@H:72]5[CH2:76][CH2:75][O:74][CH2:73]5)=[C:64]([F:77])[CH:63]=4)=[C:53](C)[CH:52]=3)[C:48]([OH:50])=O)=[CH:43][CH:44]=2)[CH:39]=[CH:38][N:37]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>CN(C)C1C=CN=CC=1.C(Cl)Cl.CN(C=O)C>[C:28]([O:32][C:33]([N:35]([C:36]1[C:45]2[C:44](=[CH:43][C:42]([NH:46][CH:47]3[C:48](=[O:50])[N:69]([CH3:70])[CH2:68][C:66]4[CH:67]=[C:62]([CH:63]=[C:64]([F:77])[C:65]=4[O:71][C@H:72]4[CH2:76][CH2:75][O:74][CH2:73]4)[NH:61][C:60](=[O:78])[O:59][CH2:58][C@H:57]([CH3:79])[C:54]4[C:53]([CH3:11])=[CH:52][C:51]3=[CH:56][CH:55]=4)=[CH:41][CH:40]=2)[CH:39]=[CH:38][N:37]=1)[C:81](=[O:82])[O:83][C:84]([CH3:85])([CH3:87])[CH3:86])=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CNCc1cc(NC(=O)OC[C@H](C)c2ccc(C(Nc3ccc4c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc4c3)C(=O)O)cc2C)cc(F)c1O[C@H]1CCOC1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc2ccc1[C@@H](C)COC(=O)Nc1cc(F)c(O[C@H]3CCOC3)c(c1)CN(C)C(=O)C2Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.8 %

Procedure:
To BOP (317 mg, 0.716 mmol), 4-dimethylaminopyridine (219 mg, 1.791 mmol) in CH2Cl2 (40 mL), was added a solution of 39E (298 mg, 0.358 mmol) in DMF (10 mL) via a syringe pump over 6 h. The mixture was stirred rt for 16 h, then concentrated and purified by prep HPLC to give 39F (180 mg, 61.7% yield). MS (ESI) m/z: 814.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[O:3].[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=O>>[F:21][C:18]([F:19])([F:20])[CH2:17][O:16][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[CH:26][C:25]1[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=1[C:23]([F:22])([F:32])[F:33]
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Product: O=C(C=Cc1ccccc1C(F)(F)F)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
The title compound was prepared from a mixture of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (200 mg, 0.633 mmol) and 2-(trifluoromethyl)benzaldehyde (83 ul, 0.633 mmol) similar to Example 6 and isolated as a pale white-yellow solid (26 mg, 9%). 1H NMR (CDCl3): 8.02 (d, J=16.5 Hz, 1H), 7.82 (d, J=7.5 Hz, 1H), 7.72 (d, J=7.5 Hz, 1H), 7.62-7.47 (m, 2H), 7.39 (d, J=15.6 Hz, 1H), 7.29 (d, J=3.3 Hz, 1H), 7.14 (dd, J=3.2, 8.9 Hz, 1H), 6.95 (d, J=9.0 Hz, 1H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[CH2:27][C:26]2[CH:25]=[C:24]([OH:28])[CH:23]=[CH:22][C:21]=2[C@@H:20]2[C@@H:11]1[C@H:12]1[C@@:16]([CH2:18][CH2:19]2)([CH3:17])[C:15](=[O:29])[CH2:14][CH2:13]1)(=[O:3])[CH3:2].[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1>[C:30]([O:28][C:24]1[CH:23]=[CH:22][C:21]2[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:29])[CH2:14][CH2:13]4)[C@H:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH2:27][C:26]=2[CH:25]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)OCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCCCC[C@@H]1Cc2cc(OC(C)=O)ccc2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12

Procedure:
A solution of 60.4 g of 7α-(5-acetoxypentyl)-3-hydroxy-estra-1,3,5(10)-trien-17-one in 300 ml of pyridine is stirred with 150 ml of acetic anhydride for 1 hour at room temperature. Then, it is precipitated with a mixture of ice/water/common salt/hydrochloric acid, taken up with ethyl acetate, washed neutral with sodium bicarbonate and common salt solution, and dried on sodium sulfate and concentrated by evaporation in a vacuum. 63.9 g of 3-acetoxy-7α-(5-acetoxypentyl)-estra-1,3,5(10)-trien-17-one is obtained as oil.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].C(O[CH:8](OCC)[CH2:9][NH:10][CH2:11][C:12]#[CH:13])C>CCOCC>[CH3:1][N:2]1[CH:8]=[CH:9][N:10]([CH2:11][C:12]#[CH:13])[C:3]1=[O:4]
Reactant: C#CCNCC(OCC)OCC
Reactant: CN=C=O
Solvent: CCOCC
Product: C#CCn1ccn(C)c1=O
Temperature: 50 °C
Yield: 77.1 %

Procedure:
Methyl isocyanate (1.3 g, 0.02 mol) was added to a stirred solution of 2,2-diethoxy-N-(2-propynyl)ethylamine (3.4 g, 0.02 mol) in ether (50 mL). After 30 min the ether was evaporated and the residue was dissolved in water (50 mL), oxalic acid (1.7 g) was added, and the solution was heated at 50° C. for 30 min. The solution was then concentrated to 10 mL and neutralized with 4N NaOH solution, and extracted with ethyl acetate (4×50 mL). The ethyl acetate was evaporated and the residue was chromatographed on silica gel to give 2.1 g of product which was recrystallized from ethyl acetate:Skellysolve B; m.p. 69°-72° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7](=[O:22])[CH2:8][NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH2:3]1.[OH:23][C:24]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(CC)CC)C>C1COCC1>[OH:23][C:24]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:25][CH2:26][CH:27]([NH:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7](=[O:22])[CH2:8][NH:9][C:10](=[O:21])[C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[CH:12]=3)[CH2:3]2)[CH2:28][CH2:29]1
Reactant: N[C@H]1CCN(C(=O)CNC(=O)c2cccc(C(F)(F)F)c2)C1
Reactant: O=C1CCC(O)(c2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCC(=O)N1CC[C@H](NC2CCC(O)(c3ccccc3)CC2)C1)c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
To a solution of the pyrrolidine intermediate from step C (0.3 g, 0.85 mmol) and the ketone from step E (0.16 g, 0.85 mmol) in THF (5 mL) was added Na(OAc)3BH (0.35 g, 2.5 mmol) followed by triethylamine (0.2 mL, 1.5 mmol). The reaction was continued at room temperature overnight and quenched by addition of a saturated NaHCO3 solution. The resulting solution was extracted with EtOAc and the EtOAc layer was dried over MgSO4 and concentrated. Separation on silica gel eluting with 10% to 30% MeOH/EtOAc provided the cis (fast moving spot) and trans (slow moving spot) isomers of the title compound. MS (M+H)+ 490.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]([C:13]3[CH:14]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=4)[CH:16]=[CH:17][CH:18]=3)[CH2:11][C:10]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:42])C=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]([C:13]3[CH:14]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([S:25]([CH3:26])=[O:42])=[CH:21][CH:20]=4)[CH:16]=[CH:17][CH:18]=3)[CH2:11][C:10]([C:27]([F:33])([F:32])[C:28]([F:29])([F:30])[F:31])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3cccc(Cl)c3)c2)cc1
Solvent: ClCCl
Product: CS(=O)c1ccc(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3cccc(Cl)c3)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
To a mixture of 1-(3-Chloro-phenyl)-5-(4′-methylsulfanyl-biphenyl-3-yl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (127.0 mg, 0.26 mmol) prepared in Example 24 in dichloromethane (5.0 mL), was slowly added meta-chloroperbenzoic acid (77%, 69.0 mg, 0.31 mmol) at 0° C. The reaction mixture was stirred at room temperature 30 minutes, quenched with a saturated solution of sodium hydrogen carbonate, and then extracted with dichloromethane three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5, 1/1) to give 61.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1>Cl>[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[O:9][C:8](=[O:10])[C:7]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C1=COCCC1
Agent: Cl
Product: O=C(OC1CCCCO1)C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
10 g (35 mmol) of triphenylacetic acid are mixed with 8.8 g (104 mmol) of 3,4-dihydro-2H-pyran and 2 drops of concentrated hydrochloric acid are added to the mixture. The solution is then stirred at 70° C. for 3 hours and working up is thereafter effected in accordance with the general procedure described in Example A. Recrystallisation from n-hexane gives a product which melts at 115° C.
Reaction SMILES: I[CH2:2][CH2:3][C:4]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][O:6][CH2:5]1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[K]>CN(C=O)C>[C:14]1([C:4]2([CH2:3][CH2:2][N:24]3[C:23](=[O:25])[C:22]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]4[C:20]3=[O:30])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][O:6][CH2:5]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ICCC1(c2ccccc2)COCc2ccccc21
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCC1(c2ccccc2)COCc2ccccc21
Temperature: 0 °C
Reaction time: 14 h
Yield: 22.8 %

Procedure:
A mixture of synthesized 4-(2-iodoethyl)-4-phenylisochroman (0.5 g) and potassium phthalimide (0.51 g) was heated in DMF (10 ml) at 60° C. with stirring for 14 hours. The reaction mixture was then poured in ice-water and the syrup separating out was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated to dryness. The residue was purified by silica gel column chromatography and recrystallized from ethyl acetate-hexane to provide the title compound (0.12 g) as colorless needless.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([CH2:18][C:19]4[N:24]=[C:23]([O:25][CH:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)[CH:22]=[CH:21][CH:20]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[C:23]([O:25][CH:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]5)[N:24]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(Cn3cnc4cc(-c5ccc(Cl)cc5)sc4c3=O)n2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1c2sc(-c3ccc(Cl)cc3)cc2ncn1Cc1cccc(OC2CCNCC2)n1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
tert-Butyl 4-[(6-{[6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl]methyl}pyridin-2-yl)oxy]piperidine-1-carboxylate (679 mg, 1.23 mmol) was dissolved in DCM (5 ml) and TFA (1 ml) added. The reaction was stirred at rt. for 40 minutes. DCM (150 ml) and sat. Na2CO3 (aq) (150 ml) were added, the phases separated and the aqueous phase extracted with DCM (150 ml). The combined organics were dried through a phase separator and evaporated in vacuo to yield the title compound as a colorless oil. Yield: 550 mg (99%). 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.63 (m, 2H), 7.55 (dd, 1H, J=8.0 Hz, J=7.4 Hz), 7.48 (s, 1H), 7.42 (m, 2H), 6.95 (d, 1H, J=7.2 Hz), 6.61 (d, 1H, J=8.2 Hz), 5.20 (s, 2H), 4.90 (m, 1H), 3.01 (m, 2H), 2.61 (m, 2H), 1.87 (m, 2H), 1.60-1.46 (m, 3H). 13C NMR (400 MHz, CDCl3) δ 163.2, 157.9, 157.1, 151.6, 151.4, 149.3, 139.8, 135.8, 131.8, 129.6, 127.8, 123.1, 121.0, 115.0, 111.3, 71.9, 50.2, 44.4, 32.6. MS (ESI+) 453.00 (M+1H+)
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[O:9]=[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.O>CS(C)=O>[O:9]1[C:10]2([CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)[CH2:2]1
Reactant: C[S+](C)(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
Trimethylsulfoxonium iodide (70 g, 0.32 mol) was gradually added to a suspension of sodium hydride (13.3 g, 0.33 mol) in dimethylsulfoxide (600 ml), and the mixture was stirred at room temperature for 1 hour. To which tert-butyl 4-oxo-piperidine-1-carboxylate (58 g, 0.291 mol) was gradually added, and the mixture was stirred at 55° C. for 1 hour. The reaction mixture was poured into iced water, and extracted with diethyl ether. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate, and then filtered. The resultant filtrate was concentrated under a reduced pressure, and the residue was crystallized from n-hexane to afford tert-butyl 1-oxa-6-azaspiro[2,5]octane-6-carboxylate (61.7 g, yield 96%) as a white powder.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:19])[NH:11][C:12]1([CH3:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[CH2:2]([O:9][C:10](=[O:19])[NH:11][C:12]1([CH3:18])[CH2:17][CH2:16][N:15]([C:20]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[O:27])[CH2:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: CC1(NC(=O)OCc2ccccc2)CCNCC1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(NC(=O)OCc2ccccc2)CCN(C(=O)c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (4-methyl-piperidin-4-yl)-carbamic acid benzyl ester hydrochloride salt (0.15 g, 0.53 mmol, Example 30B) in dichloromethane (3 mL) at room temperature was added isonicotinoyl chloride (0.4 g, 2.79 mmol) and triethylamine (0.17 mL, 1.2 mmol). The reaction mixture was stirred at room temperature for 3 hours, aqueous ammonium chloride was added, and the mixture was extracted with dichloromethane (2×). Combined organic layers were washed with 10% KHSO4, sat. NaHCO3, and brine before drying (MgSO4), and concentration under reduced pressure to provide (4-methyl-1-(pyridine-4-carbonyl)-piperidin-4-yl)-carbamic acid benzyl ester. MS (CI) m/z 354 (M+1)+; 1H NMR (300 MHz, CDCl3) δ ppm 8.69 (d, 2H), 7.40-7.31 (m, 7H), 5.06 (s, 2H), 4.15 (m, 1H), 4.62 (m, 4H), 2.12 (m, 2H), 1.77-1.45 (m, 2H), 1.42 (s, 3H).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:4](=[O:22])[C:3]=1[C:23](=O)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N+:31]([O-:33])=[O:32].O.[NH2:36][NH2:37].C(=O)([O-])O.[Na+]>CN(C=O)C>[N+:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][C:23]1[C:3]2[C:4](=[O:22])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:21])[F:20])[CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:37][N:36]=1)([O-:33])=[O:32]
Reactant: NN
Reactant: O=C(Cc1ccccc1[N+](=O)[O-])c1c(O)c2cccnc2n(-c2cccc(C(F)(F)F)c2)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(Cc3ccccc3[N+](=O)[O-])n[nH]c2c2cccnc2n1-c1cccc(C(F)(F)F)c1
Temperature: 115 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-hydroxy-3-(2-nitrophenylacetyl)-1-(3-trifluoromethylphenyl)-1,8-naphthyridin-2(1H)-one (619 mg, 1.3 mmol) produced in Synthesis Example 37 in DMF (6 mL) was added hydrazine monohydrate (purity of 80%, 233 μL), and the mixture was stirred at 110 to 120° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, washed with water, and dried to give 3-(2-nitrobenzyl)-5-(3-trifluoromethylphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one as a form of crystal (565 mg, yield 92%).