Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([CH3:20])[CH:11]=1.[OH:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])=[CH:24][CH:23]=1.O>CN(C)C=O>[CH3:20][C:12]1[CH:11]=[C:10]([CH2:9][O:21][C:22]2[CH:37]=[CH:36][C:25]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[CH:24][CH:23]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Reactant: Cc1cc(CCl)c2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(COc2ccc(C(=O)OCc3ccccc3)cc2)c2ccccc2n1
Temperature: 60 °C
Yield: 42.9 %

Procedure:
3.6 g (26.3 mmol) of potassium carbonate, 5 g (21.9 mmol) of 4-chloromethyl-2-methylquinoline hydrochloride and 5.2 g (23 mmol) of benzyl 4-hydroxybenzoate are put into solution in 30 ml of dimethylformamide. The reaction medium is heated at 60° C. for 18 h then water is added. After extracting with ethyl acetate, the organic phase is washed with water then with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated under vacuum. The crude product is purified by chromatography over silica gel eluted with a 70/30 heptane/ethyl acetate mixture. 3.6 g (43%) of benzyl 4-(2-methylquinolin-4-ylmethoxy)benzoate are obtained in the form of a light-yellow solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][C:17]1[C:22]([CH3:23])=[C:21]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:19][C:18]=1O.C(N(CC)CC)C.Cl>ClCCl>[CH3:16][C:17]1[C:22]([CH3:23])=[C:21]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:19][C:18]=1[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4]
Reactant: Cc1c(O)ccc([N+](=O)[O-])c1C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(OS(=O)(=O)C(F)(F)F)ccc([N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
Trifluoromethanesulfonic anhydride (1.57 mL, 8.77 mmol) was added to 2,3-dimethyl-4-nitrophenol (1.12 g, 6.70 mmol) and triethylamine (2.5 mL, 17.9 mmol) in dichloromethane (40 mL) at 0° C. under Ar atmosphere and the resulting mixture was allowed to stir overnight at r.t. 2M HCl (50 mL) was then added and the solution was extracted with dichloromethane (3×100 mL). The organic extracts were combined, washed with saturated aqueous NaHCO3 (100 mL), diluted with n-heptane (200 mL), and passed through a pad of silica gel to give 1.96 g (98%) of 195JP07 as a yellow oil.
Reaction SMILES: FC(F)(OC1C=CC(N=NC2C=CC(N)=CC=2)=CC=1)[C:3]([F:6])([F:5])[F:4].[CH2:24]([O:26][C@@H:27]1[C@@H:32]([O:33][CH3:34])[C@H:31]([CH3:35])[O:30][C@@H:29]([O:36][C:37](=[O:61])[NH:38][C:39]2[CH:44]=[CH:43][C:42]([N:45]=[N:46][C:47]3[CH:52]=[CH:51][C:50]([O:53]C(F)(F)C(F)(F)F)=[CH:49][CH:48]=3)=[CH:41][CH:40]=2)[C@@H:28]1[O:62][CH3:63])[CH3:25]>>[CH2:24]([O:26][C@@H:27]1[C@@H:32]([O:33][CH3:34])[C@H:31]([CH3:35])[O:30][C@@H:29]([O:36][C:37](=[O:61])[NH:38][C:39]2[CH:44]=[CH:43][C:42]([N:45]=[N:46][C:47]3[CH:52]=[CH:51][C:50]([O:53][C:3]([F:6])([F:5])[F:4])=[CH:49][CH:48]=3)=[CH:41][CH:40]=2)[C@@H:28]1[O:62][CH3:63])[CH3:25]
Reactant: Nc1ccc(N=Nc2ccc(OC(F)(F)C(F)(F)F)cc2)cc1
Reactant: CCO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](OC(=O)Nc2ccc(N=Nc3ccc(OC(F)(F)C(F)(F)F)cc3)cc2)[C@@H]1OC
Product: CCO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](OC(=O)Nc2ccc(N=Nc3ccc(OC(F)(F)F)cc3)cc2)[C@@H]1OC

Procedure:
4-(4-Pentafluoroethoxyphenylazo)aniline 1H NMR (300 MHz, CDCl3) δ7.89-7.79 (m, 4H), 7.32 (d, J=8.5 Hz, 2H), 6.73-6.76 (m, 2H), 4.09 (br s, 2H); ESIMS m/z 332 ([M+H]+). Step 2. Compound 22. 1H NMR (300 MHz, CDCl3) δ 7.96-7.92 (m, 4H), 7.60-7.57 (m, 2H), 7.38-7.35 (m, 2H), 6.86 (s, 1H), 6.26 (s, 1H), 3.75-3.45 (m, 11H), 3.22 (t, J=9.3 Hz, 1H), 1.33-1.26 (m, 6H); ESIMS m/z 578 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[F:12][C:13]1[CH:14]=[CH:15][C:16]([N+:23]([O-:25])=[O:24])=[C:17]([S:19](Cl)(=[O:21])=[O:20])[CH:18]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:12][C:13]1[CH:14]=[CH:15][C:16]([N+:23]([O-:25])=[O:24])=[C:17]([S:19]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)(=[O:20])=[O:21])[CH:18]=1
Reactant: Nc1cccc2cccnc12
Reactant: O=[N+]([O-])c1ccc(F)cc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(F)cc1S(=O)(=O)Nc1cccc2cccnc12
Yield: 24.6 %

Procedure:
In a similar fashion using route 18 general procedure 27, 8-aminoquinoline (1.6 g, 11.1 mmol), 5-fluoro-2-nitro-benzenesulfonyl chloride (Intermediate 450) (3.4 g, 14.4 mmol), pyridine (4.48 ml, 55.5 mmol), DMAP (cat.) and DCM (6 ml) gave the title compound (0.95 g, 25%) after purification by column chromatography with n-hexane/DCM (50:50) as the eluent. The structure was confirmed by 1H NMR.
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:26])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[N:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]2)=[CH:15][C:14]=1[CH2:13]3)=[O:11].[CH2:27](O)[CH2:28]C.OO>S(=O)(=O)(O)O>[CH3:27][CH2:28][C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:22]=[C:23]2[C:14]=1[CH2:13][N:12]1[C:10](=[O:11])[C:5]3[CH2:6][O:7][C:8]([C@:3]([OH:26])([CH2:2][CH3:1])[C:4]=3[CH:25]=[C:24]12)=[O:9]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Reactant: CCCO
Agent: O=S(=O)(O)O
Agent: OO
Product: CCc1c2c(nc3ccccc13)-c1cc3c(c(=O)n1C2)COC(=O)[C@]3(O)CC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In an aqueous solution of sulfuric acid (15 ml of concentrated sulfuric acid in 30 ml of water) were dissolved camptothecin (1.00 g, 2.87 m-mol), ferrous sulfate heptahydrate (5.60 g, 20.1 m-mol) and 1-propanol (6 ml, 86.1 m-mol). To this solution was added dropwise under ice-cooling and agitation a 30% aqueous solution of hydrogen peroxide (2.1 ml, 20.1 m-mol) in small portions. After addition of the hydrogen peroxide, the agitation was continued for one hour at room temperature. The reaction was diluted with ice water (2 l) and extracted with chloroform (2.5 l). The chloroform layer was dried with anhydrous magnesium sulfate, filtered and evaporated until dryness under reduced pressure. The residue was subjected to column chromatography (chloroform) through silica gel (15 g) to effect separation and purification of the product which was then recrystallized from n-hexane-chloroform whereby 265 mg (25.3%) of the objective compound were obtained as light yellow white needle crystals. M.P. 258°-261° C.
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.Cl.[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[C:20]([C:22]3[CH:31]=[C:30]4[C:25]([CH2:26][CH2:27][NH:28][CH2:29]4)=[CH:24][CH:23]=3)[N:19]=[C:18]([NH2:32])[N:17]=2)[CH2:12][CH2:11]1>>[CH:1]1([C:5]([N:28]2[CH2:27][CH2:26][C:25]3[C:30](=[CH:31][C:22]([C:20]4[CH:21]=[C:16]([N:13]5[CH2:12][CH2:11][N:10]([CH3:9])[CH2:15][CH2:14]5)[N:17]=[C:18]([NH2:32])[N:19]=4)=[CH:23][CH:24]=3)[CH2:29]2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: O=C(Cl)C1CCC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)C3CCC3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared from cyclobutanecarboxylic acid chloride and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt using procedures analogous to those for Example 2. Analytic LCMS (M+H)+: m/z=407.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH3:23])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][C:20](O)=[O:21])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH3:23])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][C:20]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:21])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(CC(=O)O)c2)=C(C)C1=O
Reactant: C1COCCN1
Product: COC1=C(OC)C(=O)C(Cc2cccc(CC(=O)N3CCOCC3)c2)=C(C)C1=O
Yield: 37 %

Procedure:
3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenylacetic acid (90 mg, 0.27 mmol) obtained in Example 57 and morpholine (0.035 ml, 0.41 mmol) were used, and a method similar to that described in Example 46 was employed to obtain the title compound (41 mg, 0.10 mmol, yield 37%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.O.[C-:11]#[N:12].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:11]#[N:12]
Reactant: [C-]#N
Reactant: BrCc1ccccc1Br
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1ccccc1Br
Temperature: 0 °C
Yield: 96.4 %

Procedure:
25 g (100 mmol) of 2-bromobenzyl bromide is mixed in 100 ml of N,N-dimethylformamide and 64 ml of water with 9.75 g (150 mmol) of potassium cyanide and stirred overnight at room temperature. The reaction mixture is poured into ice water. After 3× extraction with methyl-tert butyl ether, the combined organic extracts are washed with brine, dried, and the solvent is spun off. The residue is chromatographed on silica gel (mobile solvent ethyl acetate/hexane). 18.9 g (96.4%) of the desired compound is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[O:5][CH2:6][CH2:7]O.CN1CCOCC1.CS(Cl)(=O)=O.[CH2:24]([NH2:27])[CH2:25][NH2:26]>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[O:5][CH2:6][CH2:7][NH:26][CH2:25][CH2:24][NH2:27]
Reactant: OCCOc1cccc(Br)c1
Reactant: NCCN
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: NCCNCCOc1cccc(Br)c1

Procedure:
To a magnetically stirred, ambient temperature solution of 2-(3-bromo-phenoxy)-ethanol (3.6 g, 16.7 mmol) and N-methylmorpholine [109-02-4] (2.2 mL, 20.0 mmol) in ethyl acetate (200 mL) was added methanesulfonyl chloride [124-63-0] (1.3 mL, 16.8 mmol). The reaction was stirred over night then washed with brine and the phase separated ethyl acetate extract dried (MgSO4) and added to a stirred ambient temperature solution of ethylenediamine [107-15-3] (33.3 mL, 497.0 mmol) in ethyl acetate (300 mL) from a pressure equalizing addition funnel over the course of 15 minutes. The addition funnel was replaced with a condenser and the reaction refluxed for 4 h then cooled and washed with brine. The ethyl acetate phase was dried (CaSO4) and evaporated to obtain N1-(2-(3-bromophenoxy)ethyl)ethane-1,2-diamine as 4.7 g of clear yellow liquid. LRMS (ESI) m/z 259.1/261.1 [(M+H)]+, calc'd for C10H15BrN2O: 259.15.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:12])[C:4](=[O:13])[C:3]=1[N+:14]([O-])=O>[Pd].CCO.C1COCC1>[NH2:14][C:3]1[C:4](=[O:13])[N:5]([CH3:12])[C:6]2[C:11]([C:2]=1[NH2:1])=[CH:10][CH:9]=[CH:8][N:7]=2
Reactant: Cn1c(=O)c([N+](=O)[O-])c(N)c2cccnc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1c(=O)c(N)c(N)c2cccnc21
Reaction time: 2 h
Yield: 94.3 %

Procedure:
A solution of 4-amino-1-methyl-3-nitro-1H-[1,8]naphthyridin-2-one (1.35 g, 6.13 mmol) in 1:1 EtOH/THF (25 mL) was hydrogenated over 10% Pd/C (1.30 g, 1.23 mmol) at room temperature. After 2 h, the catalyst was removed by filtration, rinsing with MeOH. The filtrate was concentrated to provide 3,4-diamino-1-methyl-1H-[1,8]naphthyridin-2-one (1.10 g, 94% yield). 1H-NMR (DMSO): δ 8.39 (dd, 1H, J=4.8, 1.6 Hz), 8.19 (dd, 1H, J=6.4, 1.6 Hz), 7.24 (dd, 1H, J=8.0, 4.8 Hz), 5.58 (s, 2H), 4.52 (s, 2H), 3.69 (s, 3H). MS: calculated for C9H10N4O+H 191.1; found: 191.2.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([N:6]1[C@H:10]([C:11]([OH:13])=[O:12])[C@@H:9]([CH3:14])[O:8][CH2:7]1)=[O:5].[OH-:15].[Na+].II>O.C(O)C>[O:15]=[C:4]([N:6]1[C@H:10]([C:11]([OH:13])=[O:12])[C@H:9]([CH3:14])[O:8][CH2:7]1)[CH2:3][CH2:2][S:1][S:1][CH2:2][CH2:3][C:4]([N:6]1[CH:10]([C:11]([OH:13])=[O:12])[CH:9]([CH3:14])[O:8][CH2:7]1)=[O:5]
Reactant: C[C@H]1OCN(C(=O)CCS)[C@@H]1C(=O)O
Reactant: [OH-]
Agent: II
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1OCN(C(=O)CCSSCCC(=O)N2CO[C@@H](C)[C@H]2C(=O)O)C1C(=O)O

Procedure:
(4S-trans)-3-(3-Mercapto-1-oxopropyl)-5-methyl-4-oxazolidinecarboxylic acid from Example 1 is dissolved in water and the pH is adjusted to about 6.5 with 1 N sodium hydroxide. To this stirred solution is added dropwise 0.5 M iodine solution in 95% ethanol (6.34 g., iodine/50 ml. solution) while maintaining the pH at 5.5 to 6.5 with 1 N sodium hydroxide. Excess iodine is removed from the reaction mixture with dilute sodium thiosulfate and the solution is then concentrated, cooled and acidified with 1:1 hydrochloric acid. Solvent is added and the mixture is saturated with sodium chloride, stirred, and the layers separated. The organic layer is dried and the solvent evaporated to yield (S,S)-3,3'-[dithiobis(1-oxo-3,1-propanediyl)]bis[5-methyl-4-oxazolidinecarboxylic acid].
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[C:22]([F:23])=[CH:21][C:11]([O:12][CH2:13][CH2:14][CH2:15]OS(C)(=O)=O)=[CH:10][C:9]=2[F:24])[C:6](=[O:25])[CH:5]=[CH:4][C:3]=1[C:26](=[O:35])[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[F:34].[C:36]([O:40][C:41](=[O:48])[C@@H:42]([CH2:44][CH:45]([CH3:47])[CH3:46])[NH2:43])([CH3:39])([CH3:38])[CH3:37]>>[NH2:1][C:2]1[N:7]([C:8]2[C:22]([F:23])=[CH:21][C:11]([O:12][CH2:13][CH2:14][CH2:15][NH:43][C@@H:42]([C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:48])[CH2:44][CH:45]([CH3:46])[CH3:47])=[CH:10][C:9]=2[F:24])[C:6](=[O:25])[CH:5]=[CH:4][C:3]=1[C:26](=[O:35])[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[F:34]
Reactant: CC(C)C[C@@H](N)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)OCCCOc1cc(F)c(-n2c(N)c(C(=O)c3ccc(F)cc3F)ccc2=O)c(F)c1
Product: CC(C)C[C@@H](NCCCOc1cc(F)c(-n2c(N)c(C(=O)c3ccc(F)cc3F)ccc2=O)c(F)c1)C(=O)OC(C)(C)C

Procedure:
From Intermediate 4F and D-Leucine tert-butyl ester, LCMS purity 95%, m/z 606 [M+H]+, 1H NMR (300 MHz, DMSO), δ: 9.30-9.00 (2H, m), 7.62-7.52 (1H, m), 7.47-7.32 (2H, m), 7.28-7.12 (1H, m), 7.06 (2H, d, J=10.2 Hz), 5.73 (1H, d, J=9.6 Hz), 4.20 (2H, t, J=5.7 Hz), 3.99 (1H, br s), 3.25-2.95 (2H, m), 2.20-2.05 (2H, m), 1.80-1.60 (3H, m), 1.49 (9H, s), 0.95 (6H, d, J=4.8 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][NH:13][CH3:14]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:13]([CH3:14])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CNC
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1ccc(F)cc1

Procedure:
A solution of 38.9 g (0.20 mole) of 4-fluorobenzenesulfonylchloride in 20 ml of methylene chloride was added slowly to 300 ml of a 40% aqueous dimethylamine solution during 0.5 hour period. The reaction was exothermic. After the reaction mixture was cooled a yellow solid was precipitated. The solid was collected, dissolved in 300 ml of ethyl acetate, and dried over magnesium sulfate. The solution was concentrated to 100 ml and a light yellow crystal formed. The crystal was collected and air-dried to afford 39 g of the product, mp 40°-43° C.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].[I-].[Na+].Cl[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:14]([CH2:41][CH2:42][CH3:43])[N:15]=[C:16]2[C:25]=1[C:24]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:18]=[C:17]2[N:26]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>CN(C=O)C>[C:1]([O:4][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:14]([CH2:41][CH2:42][CH3:43])[N:15]=[C:16]2[C:25]=1[C:24]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:18]=[C:17]2[N:26]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CCCn1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3ccccc3c2c1CCCCCl
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3ccccc3c2c1CCCCOC(C)=O
Temperature: 90 °C
Yield: 77.1 %

Procedure:
Potassium acetate (0.83 g, 8.432 mmol) and sodium iodide (16 g, 1.05 mmol) was added to a solution of di(tert-butyl) 1-(4-chlorobutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate (2.18 g, 4.22 mmol) in DMF (15 mL). The reaction mixture was heated at 90° C. under a nitrogen atmosphere for 4.5 hours. The reaction was allowed to cool to ambient temperature and the volatiles were removed under reduced pressre. The resulting oil was partitioned between ethyl acetate and water. The organic layer was isolated and washed with water (2×25 mL) and brine (3×20 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield an oil that was dried under vacuum to provide 1.76 g of 4-{4-[bis(tert-butoxycarbonyl)amino]-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl}butyl acetate.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:4](/[CH:5]=[CH:6]\[C:7]([O:9]C)=[O:8])[CH:3]1[C:11]([OH:13])=[O:12].N1[C:24]2[C:19](=[CH:20]C=CC=2)[CH:18]=CC=1>[OH-].[Pd+2].[OH-].C(OCC)(=O)C>[CH3:1][C:2]1([CH3:14])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([OH:9])=[O:8])[C@H:3]1[C:11]([O:13][C:19]([CH3:24])([CH3:20])[CH3:18])=[O:12]
Reactant: COC(=O)/C=C\C1C(C(=O)O)C1(C)C
Reactant: c1ccc2ncccc2c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@@H]1[C@H](/C=C\C(=O)O)C1(C)C

Procedure:
A mixture of 2 g of tert.-butyl (1R, cis) 2,2-dimethyl-3-[Z-carboxyethynyl]-cyclopropane-carboxylic acid, 40 ml of ethyl acetate, 0.38 g of 10% palladium hydroxide on barium sulfate and 0.4 ml of quinoline was hydrogenated and was filtered. The filtrate was washed with 0.5 N hydrochloric acid and with water until the wash water was neutral, dried and evaporated to dryness under reduced pressure to obtain 2 g of tert.-butyl (1R,cis) 2,2-dimethyl-3-[Z-2-carboxyethenyl]-cyclopropane-carboxylate melting at 94° C.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)=O.[C:18](=O)([O-])[O-:19].[K+].[K+]>CN(C)C=O>[CH:18]([C:12]1[C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][N:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12)=[O:19]
Reactant: O=C([O-])[O-]
Reactant: CC(C)c1cc2ccccn2n1
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)c1nn2ccccc2c1C=O
Temperature: 0 °C
Yield: 67 %

Procedure:
One gram of 2-isopropylpyrazolo[1,5-a]pyridine was dissolved in 0.6 ml of dimethylformamide, and 5 ml of phosphorus oxychloride was added to the resulting solution. The reaction mixture was refluxed for 20 min., poured into ice-water, and neutralized with potassium carbonate. The precipitate was collected by filtration and washed with water. Recrystallization from n-hexane gave 800 mg of colorless needles, mp 81.0°-81.5°. Yield 67%.
Reaction SMILES: C12NC(COC1)CC1O[N:4]=[CH:3]C2=1.[OH:13][CH:14]1[C:21](=[O:22])[CH2:20][CH:19]2[N:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:15]1[CH2:16][O:17][CH2:18]2>>[C:27]([O:26][C:24]([N:23]1[CH:15]2[CH2:16][O:17][CH2:18][CH:19]1[C:20]1[CH:3]=[N:4][O:22][C:21]=1[CH:14]2[OH:13])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: c1noc2c1C1COCC(C2)N1
Reactant: CC(C)(C)OC(=O)N1C2COCC1C(O)C(=O)C2
Product: CC(C)(C)OC(=O)N1C2COCC1C(O)c1oncc12

Procedure:
7-Hydroxy-5,10-dioxa-4,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-diene-12-carboxylic acid tert-butyl ester 106d was prepared in analogy to compound 105a in Example 105, starting with 106c (260 mg). 141 mg of 106d was obtained as a colorless oil. MS: calc'd (MH+) 283, measured (MH+) 283.
Reaction SMILES: C(C1C=C2C(C3C(=O)C4C=CC([O:22][S:23]([C:26]([F:29])([F:28])[F:27])(=O)=[O:24])=CC=4C(C)(C)C=3N2)=CC=1)#N.[CH2:31]([C:33]1[C:54]([OH:55])=[CH:53][C:36]2[C:37]([CH3:52])([CH3:51])[C:38]3[NH:39][C:40]4[N:41]=[C:42]([C:49]#[N:50])[CH:43]=[CH:44][C:45]=4[C:46]=3[C:47](=[O:48])[C:35]=2[CH:34]=1)[CH3:32]>>[C:49]([C:42]1[CH:43]=[CH:44][C:45]2[C:46]3[C:47](=[O:48])[C:35]4[CH:34]=[C:33]([CH2:31][CH3:32])[C:54]([O:55][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:24])=[O:22])=[CH:53][C:36]=4[C:37]([CH3:52])([CH3:51])[C:38]=3[NH:39][C:40]=2[N:41]=1)#[N:50]
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: CCc1cc2c(cc1O)C(C)(C)c1[nH]c3nc(C#N)ccc3c1C2=O
Product: CCc1cc2c(cc1OS(=O)(=O)C(F)(F)F)C(C)(C)c1[nH]c3nc(C#N)ccc3c1C2=O

Procedure:
According to the method used for synthesizing Compound B1, 7-ethyl-8-hydroxy-10,10-dimethyl-5-oxo-10,11-dihydro-5H-1,11-diaza-benzo[b]fluorene-2-carbonitrile was subjected to trifluoromethanesulfone esterification to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[CH3:11][C:12]([O:15][C:16](=[O:26])[N:17]([CH2:19][CH2:20][CH:21]([OH:25])[CH2:22][CH2:23][CH3:24])[CH3:18])([CH3:14])[CH3:13]>>[CH3:13][C:12]([O:15][C:16](=[O:26])[N:17]([CH2:19][CH2:20][CH:21]([O:25][C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])[CH2:22][CH2:23][CH3:24])[CH3:18])([CH3:11])[CH3:14]
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: CCCC(O)CCN(C)C(=O)OC(C)(C)C
Product: CCCC(CCN(C)C(=O)OC(C)(C)C)Oc1cc(Cl)ccc1C#N

Procedure:
The title compound was prepared according to the method of Example 3 step (b) but using 4-chloro-2-fluorobenzonitrile and (3-hydroxyhexyl)methylcarbamic acid 1,1-dimethylethyl ester.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH3:17])[C:11](=[O:12])[NH:10][C@@H:9]2[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]2[O:7]1)=[O:5])C.[OH-].[Na+].Cl>O1CCOCC1>[CH3:17][C:6]1([C:4]([OH:5])=[O:3])[C:11](=[O:12])[NH:10][C@@H:9]2[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]2[O:7]1
Reactant: CCOC(=O)C1(C)O[C@@H]2CCCC[C@H]2NC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC1(C(=O)O)O[C@@H]2CCCC[C@H]2NC1=O
Yield: 54.5 %

Procedure:
A solution of trans-ethyl-2-methyl-3-oxo-octahydro-2H-1,4-benzoxazine-2-carboxylate (4.80 g, 19.8 mmoles) and 1N NaOH (29,7 ml, 20.7 mmoles) in dioxan (80 ml) was stirred for 20 hours. The solvent was evaporated, 1N HCl (90 ml, 90 mmoles) was added to the residue and the mixture was extracted with ethyl acetate (4×60 ml). The organic phase was dried over MgSO4, the solvent was evaporated and the product was recrystallized from ethyl acetate. Thus there were obtained 2.3 g (54,5%) of the title product in the form of white crystals, m.p. 142°-144° C.
Reaction SMILES: Br[CH2:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>CN(C)C=O.C(OCC)(=O)C>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3](=[O:13])[CH2:2][N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[CH:7][CH:8]=1
Reactant: O=C(CBr)CCc1ccc(Br)cc1
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CCc1ccc(Br)cc1)Cn1ccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
A mixture of 1-bromo-4-(4-bromophenyl)-2-butanone (0.5 mmol) and imidazole (102 mg, 1.5 mmol) in dry N,N-dimethylformamide (2 mL) was stirred at room temperature under a nitrogen atmosphere for 1 h. The mixture was then diluted with ethyl acetate (15 mL), and the solution was washed with water (4×15 mL). The separated organic phase was dried over anhydrous Na2SO4, and then the solvent was removed under reduced pressure to afford a residue that was chromatographed on a silica gel column using ethyl acetate as mobile phase to give 4-(4-bromophenyl)-1-(1H-imidazol-1-yl)-2-butanone as a white solid (111 mg, 76%): mp 79-80° C., Rf=0.50 (ethyl acetate-methanol 4:1 v/v); 1H NMR (400 MHz, CDCl3): δ 2.70 (t, J=7.2 Hz, 2H), 2.83 (t, J=7.2 Hz, 2H), 4.65 (s, 2H), 6.81 (bs, 1H), 7.02 (d, J=7.6 Hz, 2H), 7.09 (s, 1H), 7.37-7.40 (m, 3H); 13C NMR (100 MHz, CDCl3): δ 28.6, 40.9, 55.7, 120.1, 120.4, 130.0, 131.8, 138.0, 139.1, 202.3; HRMS (EI) Calcd. for C13H13BrN2O: 292.0211 (M+). Found: 292.0219.