Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)CCCCCC1.C(N1CCC(N)CC1)[C:34]1[CH:39]=[CH:38]C=[CH:36][CH:35]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH2:9]([N:10]1[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[C:25]([O:28][CH2:29][CH:30]([CH3:31])[CH3:32])[CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:12][CH2:11]1)[C:8]1[CH:38]=[CH:39][CH:34]=[CH:35][CH:36]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCCCCC4)CC3)cc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(Cc4ccccc4)CC3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Isobutoxy-1H-indole-2-carboxylic acid 80 (4.7 g, 20.1 mmol, preparation see Example 8) and 1-benzyl-piperidin-4-ylamine (4.2 ml, 20.1 mmol) are dissolved in 70 ml of DMF and after addition of TBTU (7.3 g, 22.1 mmol) and ethyldiisopropylamine (13.8 ml, 80.4 mmol) the mixture is stirred at room temperature for 2 h. Then the solvent is evaporated at high vacuum. The residue is dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and brine. The organic layers are dried over sodium sulfate and evaporated under reduced pressure.
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][C:25]([O:27]CC)=O)=[O:22])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CC(C)([O-])C.[K+].Cl>C1COCC1.CN(C=O)C>[CH2:1]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([O:23][CH2:24][C:25]=2[OH:27])=[O:22])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOc1ccc(CC(=O)OCC(=O)OCC)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOc1ccc(C2=C(O)COC2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
In a mixture of THF (50 ml) and DMF (10 ml) was dissolved ethoxycarbonylmethyl 4-dodecyloxyphenylacetate (5.0 g, 0.013 mol.). To the solution was added at room temperature potassium tertiary butoxide (2 g, 0.017 mol.). The mixture was stirred at room temperature for one hour, after which was added 2N HCl (20 ml). The resultant mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure The resultant crude crystals were recrystallized from IPE-ethyl acetate to give 2-(4-dodecyloxyphenyl)-3-hydroxy-2-buten-4-olide (4-h, 3.0 g, 70%). By a procedure analogous to the above, compounds (4-a to 4-c, 4-f, 4-j to 4-m) were synthesized. Physico-chemical properties and NMR spectra of these compounds are shown in Table 7.
Reaction SMILES: N1([O:10][C:11]2[C:12]3[N:13]=[CH:14][N:15]([C:38]=3[N:39]=[CH:40][N:41]=2)[C@@H:16]2[O:37][C@H:27]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C@@H:18]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:17]2)C2C=CC=CC=2N=N1.C([O-])([O-])=O.[Cs+].[Cs+].[C:48]1(O)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C1(C)C=CC=CC=1>[Si:30]([O:29][C@@H:28]1[C@@H:27]([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[O:37][C@@H:16]([N:15]2[C:38]3[N:39]=[CH:40][N:41]=[C:11]([O:10][C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[C:12]=3[N:13]=[CH:14]2)[CH2:17]1)([C:33]([CH3:35])([CH3:36])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(On4nnc5ccccc54)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(Oc4ccccc4)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 105 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
In a clean, dry reaction vial equipped with a stirring bar were placed O6-(benzotriazol-1-yl)-3′,5′-bis-O-(tert-butyldimethylsilyl)-2′-deoxyinosine (26) (63.2 mg, 0.106 mmol), Cs2CO3 (68.9 mg, 0.211 mmol) and phenol (19.9 mg, 0.211 mmol). Dry toluene (1.0 mL) was added and the reaction mixture was flushed with N2 and the mixture was allowed to stir at 105° C. for 2 h. The reaction mixture was filtered through Celite, the residue washed with Et2O and the filtrate evaporated to dryness. Chromatographic purification (SiO2, elution with 20% EtOAc in hexanes) afforded 50.5 mg (86% yield) of the title compound as a clear gum. Rf (20% EtOAc in hexanes)=0.21. 1H NMR (500 MHz, CDCl3): δ 8.49 (s, 1H, Ar—H), 8.40 (s, 1H, Ar—H), 7.45 (app t, 2H, Ar—H, Japp˜7.8), 7.29-7.26 (m, 3H, Ar—H), 6.53 (t, 1H, H-1′, J=6.3), 4.64 (m, 1H, H-3′), 4.04 (q, 1H, H-4′, J=3.4), 3.90 (dd, 1H, H-5′, J=11.2, 3.9), 3.70 (dd, 1H, H-5′, J=11.2, 2.7), 2.65 (app quint, 1H, H-2′, Japp˜6.3), 2.48 (ddd, 1H, H-2′, J=13.2, 6.1, 4.1), 0.92, 0.91 (2 s, 18H, tert-Bu), 0.10 (s, 12H, SiCH3). 13C NMR (126 MHz, CDCl3): δ 160.2, 152.5, 152.4, 152.0, 141.6, 129.6, 125.7, 122.1, 121.9, 88.0, 84.6, 71.8, 62.7, 41.5, 26.0, 25.7, 18.4, 18.0, −4.7, −4.8, −5.4, −5.5. FAB HRMS calcd for C28H45N4O4Si2 (M++H) 557.2979. found 557.2978.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:8][C:9]([F:12])([F:11])[CH3:10])[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.[C:19](Cl)(Cl)=[O:20]>ClCCl.C1(C)C=CC=CC=1>[F:12][C:9]([F:11])([CH3:10])[CH2:8][C@H:3]([N:2]=[C:19]=[O:20])[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C(Cl)Cl
Reactant: COC(=O)[C@@H](N)CC(C)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)[C@H](CC(C)(F)F)N=C=O
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
Under argon, 2.0 g of methyl (S)-2-amino-4,4-difluoropentanoate hydrochloride (9.8 mmol) were dissolved in 80 ml of dichloromethane, admixed with 3.2 ml of pyridine (4 eq.) and cooled to approx. 5° C. (ice bath). After 10 min, 6.7 ml (1.3 eq.) of a 20% phosgene solution in toluene were slowly added dropwise. The resulting suspension was stirred with ice bath cooling for 3 h and then concentrated under reduced pressure. The residue thus obtained was taken up in toluene and filtered. After the solvent had been removed under reduced pressure, methyl (S)-4,4-difluoro-2-isocyanatopentanoate was obtained as a brown oil which was used in the subsequent reaction without further purification. Yield: 1.1 g (58% of theory).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:23])[CH:8]=2)[N:3]=1.[C:24]1([S:30]([Cl:33])(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N1C=CC=CC=1>ClCCl.[OH-].[Na+]>[ClH:33].[CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:23][S:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:32])=[O:31])[CH:8]=2)[N:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1cc(N2CCC(c3ccccc3)C2)c2cc(N)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(N2CCC(c3ccccc3)C2)c2cc(NS(=O)(=O)c3ccccc3)ccc2n1
Product: Cl
Yield: 31.6 %

Procedure:
2-Methyl-6-amino-4-(3-phenylpyrrolidin-1-yl)quinoline (0.07 g; see Example 45 below), benzenesulfonyl chloride (0.041 g) and pyridine (0.04 g) was stirred in dichloromethane (4 mL). The reaction mixture was diluted with 1 N sodium hydroxide and extracted with ethyl acetate, washed with water, dried (MgSO4), filtered and evaporated to give a brown oil. The residue was purified by chromatography on silica, eluting with a mixture of dichloromethane, and methanol. The desired fractions were concentrated, hydrochloric acid was added, and the sample evaporated to dryness. Trituration from ether gave the title compound as a white solid (0.035 g).
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]([CH3:21])([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[C:18]([N:13]1[C:12]([C:34]2[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:19])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C(C)(C)C)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: OB(O)c1ccc(F)cc1
Product: CC(C)(C)n1nc2c(c1-c1ccc(F)cc1)CCNCC2
Yield: 66.3 %

Procedure:
The title compound (88 mg) was prepared as in Example 177, Steps C and D, using 204 mg of 2-(tert-butyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 215 Step A) and 194 mg of 4-fluorophenylboronic acid. MS (ESI): exact mass calculated for C17H22FN3, 287.18. found, m/z 288.4 [M+H]+, 232.4 [M-tBu]+. 1H NMR (500 MHz, CD3OD): 7.37-7.33 (m, 2H), 7.26-7.22 (m, 2H), 3.41-3.38 (m, 2H), 3.26-3.24 (m, 2H), 3.18-3.15 (m, 2H), 2.53-2.51 (m, 2H), 1.42 (s, 9H).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH:9]=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:11][O:12][C:13](=O)/[CH:14]=[CH:15]/[O:16]C>>[CH:1]1([CH2:7][CH2:8][CH:9]2[O:10][C:15](=[O:16])[CH:14]=[C:13]2[O:12][CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CO/C=C/C(=O)OC
Reactant: O=CCCC1CCCCC1
Product: COC1=CC(=O)OC1CCC1CCCCC1

Procedure:
Using general procedure A, cyclohexanepropanal (Stratakis, Manolis et al., Journal of Organic Chemistry (2002), 67(25), 8758-8763) was reacted with 3(E)-methoxy-acrylic acid methyl ester to give rac-5-(2-cyclohexyl-ethyl)-4-methoxy-5H-furan-2-one as a colorless solid. MS: 225.2 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:15])[N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:5]=[CH:6][C:7]=1Cl.C(=O)([O-])[O-].[K+].[K+].[C:22]1([OH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[Cl:1][C:2]1[C:3](=[O:15])[N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:5]=[CH:6][C:7]=1[O:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=c1c(Cl)c(Oc2ccccc2)cnn1C1CCCCO1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
A solution of 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20, 2.50 g, 10.03 mmol) in acetonitrile (111 mL, 0.09M) was treated with potassium carbonate (1.38 g, 10.03 mmol) and phenol (944 mg, 10.03 mmol). The resulting reaction mixture was heated at reflux for 3 h and then was allowed to cool to 25° C. The reaction mixture was then partitioned between water (150 mL) and methylene chloride (3×100 mL). The combined organics were dried over sodium sulfate, filtered, rinsed, and concentrated in vacuo. Silica gel column chromatography (ISCO 80 g, 30% ethyl acetate/hexanes) afforded 4-chloro-5-phenoxy-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (2.84 g, 92%) as a clear oil; ES+-HRMS m/e calcd for C15H15N2O3Cl [M+H+] 307.0844, found 307.0843.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([CH:22]=[CH:23][C:24]([OH:26])=[O:25])([CH2:18][CH2:19]3)[CH2:16][O:15]4)[NH:6][C:5]=2[C:4](=[O:27])[N:3]1[CH2:28][CH2:29][CH3:30]>CO.[Pd]>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])([CH2:18][CH2:19]3)[CH2:16][O:15]4)[NH:6][C:5]=2[C:4](=[O:27])[N:3]1[CH2:28][CH2:29][CH3:30]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(C=CC(=O)O)(CC3)CO4)nc2n(CCC)c1=O
Agent: [Pd]
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(C34CCC(CCC(=O)O)(CC3)CO4)nc2n(CCC)c1=O
Reaction time: 0.5 h

Procedure:
3-[-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-2-oxa-bicyclo[2.2.2]oct-4-yl]-acrylic acid was dissolved in 50 ml of MeOH. 10% Pd on C (10 mg) was added and the reaction mixture was hydrogenated at RT under 55 psi of H2 for 30 min. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to afford the title compound. MS (ES+) 419.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[C:24]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:28])[C@@H:25]([CH3:27])O.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(Cl)Cl.CO>[C:30]([O:29][C:24](=[O:28])[C@@H:25]([O:23][C:21]1[N:20]=[CH:19][C:16]2[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]=2[CH:22]=1)[CH:10]=[C:9]([C:8]1[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=1)[N:18]=3)[CH3:27])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O)cc1OCC2
Reactant: C[C@@H](O)C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O[C@@H](C)C(=O)OC(C)(C)C)cc1OCC2

Procedure:
2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol from Example 93, (+)-tert-butyl d-lactate, diisopropylazodicarboxylate (DIAD), and triphenylphosphine were reacted in THF. The crude product was subjected to flash chromatography (SiO2, gradient 0-5% methanol in DCM) to give (S)-2-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yloxy]-propionic acid tert-butyl ester as a yellow oil contaminated with triphenylphosphine oxide, no further purification was undertaken (206 mg, 49% based on NMR quantification of PPh3O). LCMS: RT=3.74 min, [M+H]+=441
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[OH:12]>C(O)(=O)C.O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[O:12]
Reactant: COc1ccc(C(O)c2ccccn2)c(Cl)c1Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(C(=O)c2ccccn2)c(Cl)c1Cl

Procedure:
α-(2,3-dichloro-4-methoxyphenyl)-2-pyridinemethanol (31.86 g) is dissolved in 600 ml of acetic acid and 100 ml of H2O. Chromic anhydride (11.0 g) is added portionwise over five minutes. After three hours the reaction mixture is poured into H2O and extracted with ether. The combined organic phase is washed well with 10% NaHCO3, then brine, and dried. Removal of the solvent under reduced pressure gives a crystalline product of (2,3-dichloro-4-methoxyphenyl)(2-pyridyl)methanone, mp 104°-107° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[C:28]([CH3:35])[CH:27]=1.[CH2:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][CH2:38][NH:37]1>>[CH3:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:16]([N:37]2[CH2:38][CH2:39][C:40]3[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:36]2)=[O:18])[N:8]([C:6]([C:29]2[CH:30]=[CH:31][C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH3:19])=[CH:27][C:28]=2[CH3:35])=[O:7])[CH2:12]1
Reactant: Cc1cc(-c2ccccc2C)ccc1C(=O)O
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: c1ccc2c(c1)CCNC2
Product: CON=C1C[C@@H](C(=O)N2CCc3ccccc3C2)N(C(=O)c2ccc(-c3ccccc3C)cc2C)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′,3-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and 1,2,3,4-tetrahydroisoquinoline, the title compound was obtained in 77% purity by HPLC. MS(ESI+): m/z=482.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:10][C:11]([O:13]C)=O)[NH2:9])[CH:5]=[CH:6][CH:7]=1.[CH3:15][N:16]=[C:17]=[O:18]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:10][C:11](=[O:13])[N:16]([CH3:15])[C:17](=[O:18])[NH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN=C=O
Reactant: COC(=O)CN(N)c1cccc(Br)c1
Solvent: CC#N
Product: CN1C(=O)CN(c2cccc(Br)c2)NC1=O
Reaction time: 1 h

Procedure:
A solution of methyl [1-(3-bromophenyl)hydrazino]acetate (2.5 g) and methyl isocyanate (1.46 ml) in acetonitrile (20 ml) was heated under reflux for 2 h. The solvent was removed in vacuo and methanol (20 ml) was added to the residue which was then treated with a solution of sodium methoxide in methanol (30 ml; from 556 mg of sodium). After 1 h at 20° the solution was neutralised with acetic and the solvent was removed in vacuo. The residue was taken into ethyl acetate (250 ml), washed with pH 6 phosphate buffer solution (250 ml), dried and evaporated. Crystallisation of the residue from System B gave the title compound (316 mg). The mother liquor was evaporated, and the resulting solid was triturated with ether to give a further quantity of the title compound (335 mg), m.p. 165°-166°, t.l.c. (ether) Rf 0.41.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[Cl:29])[C@H:12]([CH3:21])[CH2:13][CH2:14][CH2:15][S:16]([NH:19][CH3:20])(=[O:18])=[O:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(S(Cl)(=O)=O)CCCC.N1C[CH2:43][S:42][CH2:41][CH2:40]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[Cl:29])[C@H:12]([CH3:21])[CH2:13][CH2:14][CH2:15][S:16]([N:19]2[CH2:40][CH2:41][S:42][CH2:43][CH2:20]2)(=[O:17])=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CNS(=O)(=O)CCC[C@@H](C)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Reactant: C1CSCCN1
Agent: CCCCCS(=O)(=O)Cl
Product: C[C@H](CCCS(=O)(=O)N1CCSCC1)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Yield: 64 %

Procedure:
4-chloro-N-[2,5-dichlorophenyl]-N-[4[(4-thiomorpholinyl)sulfonyl]-1(R)-methylbutyl]benzenesulfonamide was prepared analogous to 4-chloro-N-[2,5-dichlorophenyl]-N-[4-[(methylamino)sulfonyl]-1(R)-methylbutyl]benzenesulfonamide by reacting (4R)-4-[2,5-dichlorophenyl][4-chlorophenyl)sulfonyl]-amino]pentylsulfonyl chloride with thiomorpholine. Yield=64%; MS (ESI+), 571 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.CO[CH:35](OC)[N:36]([CH3:38])[CH3:37]>N1C=CC=CC=1>[ClH:28].[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:19](=[O:20])[NH:18][C:15]2[CH:14]=[CH:13][C:12]([N:7]3[CH:6]=[N:5][C:4]4[C:8]3=[N:9][CH:10]=[N:11][C:3]=4[N:2]=[CH:35][N:36]([CH3:38])[CH3:37])=[CH:17][CH:16]=2)=[CH:23][C:24]=1[C:29]([F:31])([F:32])[F:30]
Reactant: COC(OC)N(C)C
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CN(C)C=Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 224.7 %

Procedure:
In 10 mL of pyridine, 463 mg (0.957 mmol) of 1-[4-(6-amino-purin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride was dissolved, and 455 mg (3.83 mmol) of dimethylformamide dimethylacetal was added thereto and the mixture solution was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and then the residue was triturated with ethyl acetate and collected by filtration, and vacuum dried. The white solid was dissolved in 10 mL of methanol and 4N hydrochloric acid and concentrated under reduced pressure. The residue was triturated with ethyl acetate, collected by filtration, and then vacuum dried to obtain 580 mg (quantitative) of N′-(9-{4-[3-(4-chloro-3-(trifluoromethyl)phenyl)ureido]phenyl}-9H-purin-6-yl)-N,N-dimethylformamidine hydrochloride (Table 1, Compound No. 95) as a white solid.
Reaction SMILES: COC[O:4][C:5]1[C:6]([C:15](=[O:17])[CH3:16])=[CH:7][C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][CH:10]=1>CC(O)C.C1COCC1>[OH:4][C:5]1[C:6]([C:15](=[O:17])[CH3:16])=[CH:7][C:8]([C:11]([F:14])([F:12])[F:13])=[N:9][CH:10]=1
Reactant: COCOc1cnc(C(F)(F)F)cc1C(C)=O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(=O)c1cc(C(F)(F)F)ncc1O
Temperature: 45 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(5-(methoxymethoxy)-2-(trifluoromethyl)pyridin-4-yl)ethanone (3.2 g, 13 mmol) and 5N (40 ml) in i-PrOH/THF (1:1, 40 ml) was stirred at 45° C. overnight. The mixture was cooled, concentrated, taken up in H2O, neutralized with saturated NaHCO3, and extracted with DCM (3×). The organic layers were combined, dried over Na2SO4, and concentrated to give the title compound as a tan solid. MS (m+1): 206.2
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[C:15]3[C:10]([C:11](=[O:25])[C:12]([C:20]([O:22]CC)=[O:21])=[CH:13][N:14]3[CH:17]3[CH2:19][CH2:18]3)=[C:9]([CH3:26])[C:8]=2[F:27])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[OH-].[Na+].C(O)C>O>[N:1]1([C:7]2[CH:16]=[C:15]3[C:10]([C:11](=[O:25])[C:12]([C:20]([OH:22])=[O:21])=[CH:13][N:14]3[CH:17]3[CH2:18][CH2:19]3)=[C:9]([CH3:26])[C:8]=2[F:27])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)c(C)c2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(F)c(N2CCNCC2)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 56.4 %

Procedure:
To ethyl 7-(1-piperazinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (23 mg) are added 10% aqueous solution of sodium hydroxide (3 ml) and ethanol (3 ml), and the mixture is refluxed for 1 hour. After cooling, the reaction mixture is diluted with water and washed with dichloromethane. The aqueous layer is made acidic with acetic acid and then made weakly alkaline with an aqueous sodium hydrogen carbonate. The resultant product is extracted with dichloromethane and the extract is dried. The solvent is distilled off under reduced pressure and to the residue is added ethanol. The precipitated crystals are filtered and recrystallized from dimethylformamide to give 7-(1-piperazinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (12 mg), as white powder, m.p. 231°-233° C.
Reaction SMILES: [O-:1]O.[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(C)[CH3:4].C=CC>>[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:1])[CH3:4].[C:6]1([OH:1])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [O-]O
Reactant: CC(C)c1ccccc1
Solvent: C=CC
Product: CC(=O)c1ccccc1
Product: Oc1ccccc1

Procedure:
Referring to FIG. 4, 8 g of the same catalyst as that in Example 1 is charged in a single catalyst bed, and 10 g/hour of the same solution as that in Example 1 containing 25% by weight of isopropylbenzene hydroperoxide and 9 g/hour of the same propylene as that in Example 1 are fed thereto. The pressure at the catalyst bed is adjusted to 7.0 MPa, and the temperature at the inlet of the catalyst bed is adjusted such that the conversion of the fed isopropylbenzene hydroperoxide becomes 99%. The results of reaction in this case are shown in Table 2, indicating that the yield of propylene decreases and produced amount of acetophenone and phenol formed by thermal decomposition of isopropylbenzene hydroperoxide increases.