Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][CH2:9][C@@H:10]3[C@@H:19]([C:20]=2[CH:21]=1)[C@H:18]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][C@@:15]1([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]1[O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])(=O)C.ClC1C=CC=[C:39]([C:43]([O:45]O)=[O:44])C=1.C(=O)(O)[O-].[Na+]>ClCCl>[C:43]([O:45][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][CH2:9][C@@H:10]3[C@@H:19]([C:20]=2[CH:21]=1)[C@H:18]([O:22][C:23](=[O:28])[C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:17][C@@:15]1([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]1[O:29][C:30](=[O:35])[C:31]([CH3:33])([CH3:32])[CH3:34])(=[O:44])[CH3:39]
Reactant: CC(=O)c1ccc2c(c1)[C@@H]1[C@@H](CC2)[C@@H]2CC[C@H](OC(=O)C(C)(C)C)[C@@]2(C)C[C@H]1OC(=O)C(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)Oc1ccc2c(c1)[C@@H]1[C@@H](CC2)[C@@H]2CC[C@H](OC(=O)C(C)(C)C)[C@@]2(C)C[C@H]1OC(=O)C(C)(C)C
Yield: 31.5 %

Procedure:
A solution of the ketone (27) (40 mg. 0.83 mmol) and m-chloroperbenzoic acid (43 mg, 0.248 mmol) in dichloromethane (1 ml) was stirred for four days at room temperature in the dark. Addition of saturated sodium bicarbonate solution was followed by the usual working up procedure with methylene chloride to give a residue which was chromatographed on silica (2 g). Elution with ether-light petroleum (1:20) gave the product (28) (39 mg, 94%), m.p. 143°-146° C. (from ether-light petroleum), νmax 1720 cm-1 (C=O), δ (250 MHz) 7.10 (1 H, d, J 8 Hz, 4-proton), 6.86 (1 H, dd, J 8 and 2.5 Hz, 3-proton), 6.71 (1 H, d, J 2.5 Hz, 1-proton), 5.35 (1 H, dt, J 10.5 and 5 Hz, 11-proton), 4.65 (1 H, dd, J 8.5 and 7.5 Hz, 17-proton), 2.82 (2 H, t, J 7 Hz, 6-proton), 2.54 (1 H, t, J 10.5 Hz, 9-proton), 2.24 (3 H, s, CH3CO), 1.21 (9 H, s, OBut), 1.19 (9 H, s, OBut), 0.89 (3 H, s, 18-CH3), M+ (ammonia chemical ionization) 516 (M+NH3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:8]([OH:10])[CH3:9])[CH:7]=1>O1CCOCC1.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: CC(O)c1cc(Br)ccc1F
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: CC(=O)c1cc(Br)ccc1F
Temperature: 25 °C
Yield: 92.1 %

Procedure:
To a solution of 1-(5-bromo-2-fluoro-phenyl)-ethanol 102 (105 g, 0.479 mol.) in dioxane (2 L) was added manganese dioxide (203 g, 2.35 mol.). The reaction mixture was heated under reflux for 5 hours. The reaction mixture was allowed to cool to room temperature. The reaction mixture was filtered through Celite (i.e., diatomaceous earth) and the solid was washed with ether (1 L). The combined filtrate was evaporated under reduced pressure to afford the 1-(5-bromo-2-fluoro-phenyl)-ethanone 103 (95.7 g, 0.441 mol.) which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][Si](C(C)(C)C)(C)C)[C:3]=1[C:4]#[N:5].[S:23](Cl)(=[O:26])(=[O:25])[NH2:24]>O>[S:23](=[O:26])(=[O:25])([O:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([NH:1][S:23](=[O:26])(=[O:25])[NH2:24])[C:3]=1[C:4]#[N:5])[NH2:24]
Reactant: NS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCCCCOc1cccc(N)c1C#N
Solvent: O
Product: N#Cc1c(NS(N)(=O)=O)cccc1OCCCCOS(N)(=O)=O
Yield: 63 %

Procedure:
Prepared as in Example 197a from 2-amino-6-(4-(tert-butyldimethylsilyloxy)butoxy)benzonitrile (Example 211b) and sulfamoyl chloride in 63% yield. MS 382 (M++H2O).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([CH3:13])[CH:7]=1>OS(O)(=O)=O>[F:5][C:6]1[C:12]([N+:1]([O-:4])=[O:2])=[CH:11][C:9]([NH2:10])=[C:8]([CH3:13])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(F)ccc1N
Agent: O=S(=O)(O)O
Product: Cc1cc(F)c([N+](=O)[O-])cc1N
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 73.5 %

Procedure:
Concentrated nitric acid (17 g, 0.18 mol) was added dropwise to a stirred solution of 4-fluoro-2-methylaniline (20 g, 0.16 mol) in cone H2SO4 (300 mL) at −10° C. The mixture was stirred at −10° C. for 10 min., and the reaction mixture was poured into ice water. The resultant solid was collected by filtration and partitioned between EtOAc and aq Na2CO3 solution (pH 8). The organic solution was washed with brine, dried (MgSO4) and concentrated to give 4-fluoro-2-methyl-5-nitroaniline (20 g, 74% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.27 (d, J=6.8 Hz, 1 H), 7.14 (d, J=12.4 Hz, 1 H) 5.37 (s, 2 H), 2.10 (s, 3 H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11](=[O:20])[NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]1)([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>ClCCl.C(=O)([O-])O.[Na+]>[C:6]([O:10][C:11]([NH:12][C@H:13]1[CH2:14][CH2:15][C@H:16]([O:19][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:17][CH2:18]1)=[O:20])([CH3:9])([CH3:7])[CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OS(C)(=O)=O)CC1
Temperature: 2 °C
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (135 μl, 1.74 mmol) was added to a cooled (ice bath, 0-4° C.), stirred solution of trans-(4-hydroxycyclohexyl)carbamic acid tert-butyl ester (0.25 g, 1.16 mmol) and triethylamine (243 μl, 1.74 mmol) in dichloromethane (10 ml). Following the addition the reaction was stirred at this temperature for 30 minutes before being allowed to warm to ambient temperature. After stirring at ambient temperature for 2 hours, aqueous sodium hydrogen carbonate (10 ml) was added, followed by vigorous stirring for 30 minutes. The reaction was diluted with dichloromethane (20 ml) and aqueous sodium hydrogen carbonate (20 ml) and after partitioning the organic phase was washed with water (20 ml), dried (magnesium sulphate) and evaporated to dryness under reduced pressure to yield methanesulfonic acid trans-4-tert-butoxycarbonylaminocyclohexyl ester (340 mg, 100%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[NH:10]2)=[C:5]([S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])[CH:4]=1)#[N:2].[CH3:34][Si](C)(C)[N-][Si](C)(C)C.[Li+].IC>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[N:10]2[CH3:34])=[C:5]([S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])[CH:4]=1)#[N:2]
Reactant: CCS(=O)(=O)c1cc(C#N)ccc1[C@H]1NC(=O)N(c2cccc(C(F)(F)F)c2)C(C)=C1C#N
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCS(=O)(=O)c1cc(C#N)ccc1[C@@H]1C(C#N)=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N1C
Reaction time: 0.33 h
Yield: 82 %

Procedure:
The reaction was carried out under argon. (4S)-4-[4-Cyano-2-(ethylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (71.2 mg, 0.15 mmol) was initially charged in absolute THF (6 ml), and a 1 M solution of lithium hexamethyldisilazide (LiHMDS) in THF (180 μl; 1.2 eq.) was added at −78° C. After 20 min of stirring, iodomethane (47 μl; 5 eq.) was added, and the mixture was stirred with gradual warming from −78° C. to RT for 60 h. The reaction mixture was then purified directly by preparative HPLC (column: Gromsil, C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→80:20). This gave the title compound as a colorless solid (60 mg, 82% of theory).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][C:5]1[C:19]([C:20]2[C:21](=[O:36])[NH:22][C:23](=[O:35])[C:24]=2[C:25]2[C:33]3[C:28](=[C:29]([CH3:34])[CH:30]=[CH:31][CH:32]=3)[NH:27][CH:26]=2)=[C:8]2[CH:9]=[C:10]([CH2:13]OS(C)(=O)=O)[CH:11]=[CH:12][N:7]2[N:6]=1>>[CH3:1][N:2]([CH2:13][C:10]1[CH:11]=[CH:12][N:7]2[N:6]=[C:5]([CH3:4])[C:19]([C:20]3[C:21](=[O:36])[NH:22][C:23](=[O:35])[C:24]=3[C:25]3[C:33]4[C:28](=[C:29]([CH3:34])[CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)=[C:8]2[CH:9]=1)[CH3:3]
Reactant: Cc1nn2ccc(COS(C)(=O)=O)cc2c1C1=C(c2c[nH]c3c(C)cccc23)C(=O)NC1=O
Reactant: CNC
Product: Cc1nn2ccc(CN(C)C)cc2c1C1=C(c2c[nH]c3c(C)cccc23)C(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 62.6 %

Procedure:
Dimethylamine (approx. 50% solution in DMF, 0.04 ml, 0.27 mmol, 2.0 equiv) is added at room temperature under an atmosphere of argon to a solution of methanesulfonic acid 2-methyl-3-[4-(7-methyl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-pyrazolo[1,5-a]pyridin-5-ylmethyl ester (80 mg, 0.17 mmol). The reaction mixture is stirred at room temperature for 20 minutes. After dilution with water, the mixture is extracted three times with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (CH2Cl2/MeOH 95:5) affords the title compound (44 mg, 62%). 1H NMR (400 MHz, d6-DMSO): δ=11.77 (s, 1H), 10.93 (s, 1H), 8.48 (d, J=6.9Hz, 1H), 7.94 (d, J=3.0 Hz, 1H), 6.79 (br s, 1H), 6.74 (d=7.1 Hz, 1H), 6.65 (dd, J=7.1/1.7 Hz, 1H), 6.45 (t, J=7.1 Hz, 1H), 6.11 (d, J=8.1 Hz, 1H), 4.10 (q, J=5.4 Hz, 2H), 3.18 (s, 3H), 3.17 (s, 3H), 2.39 (s, 3H), 2.20 (s, 3H). MS (ES+): 414 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:18]=[CH:17][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:19]([N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:17][CH:18]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccccc1
Reactant: CNCCc1ccc(Oc2ccc(O)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CN(CCc1ccc(Oc2ccc(O)cc2)cc1)Cc1ccccc1

Procedure:
According to scheme 1, ethyl chloroformate is added to a solution of tyramine (1), sodium hydroxide, and water to produce the [2-(4-hydroxy-phenyl)-ethyl]-carbamic acid ethyl ester (2). The carbamate is treated with cesium carbonate and 4-fluorobenzonitrile in DMF to yield the corresponding biarylether 3. The nitrile functionality of the biaryl; ether 3 is converted to the N-acyl compound 4 by reaction with methyllithium followed by hydrolysis in aqueous sulfuric acid. The N-acyl compound 4 is converted to the acetate 5 by oxidation with m-chloroperbenzoic acid (MCPBA) in a suitable solvent. The acetate 5 is reduced with lithium aluminum hydride to afford the compound 4-[4-(2-methylamino-ethyl)-phenoxy]-phenol (6). The compound 6 is treated with benzaldehyde in the presence of sodium triacetoxyborohydride to produce the reductive amination product 4-{4-[2-(benzyl-methyl-amino)-ethyl]-phenoxy}-phenol 7 of formula I. Compounds of formula I wherein D is acetate and q is 0, may also be prepared according to scheme 2 below.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:16]([CH3:26])[CH:15]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>>[CH3:26][C:16]1[CH:15]=[C:14]([CH:12]([N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:27]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:28])[C:7]=3[CH2:8]2)[CH3:13])[CH:19]=[CH:18][C:17]=1[O:20][CH2:21][C:22]([F:25])([F:24])[F:23]
Reactant: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)ccc1OCC(F)(F)F
Reactant: O=COc1ccccc1
Product: Cc1cc(C(C)N2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)ccc1OCC(F)(F)F
Yield: 73 %

Procedure:
The title compound is prepared in 73% yield (90 mg, yellow oil) from 4-chloro-2-(1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (100 mg, 0.26 mmol, Intermediate-42, single enantiomer) and phenyl formate (64 mg, 0.52 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.S(Cl)([Cl:19])(=O)=O.[OH-].[Na+]>C(Cl)Cl.CO>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH:5]([Cl:19])[C:6](=[O:14])[C:7]1[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=1
Reactant: COC(=O)CCC(=O)c1ccc(C)cc1
Reactant: O=S(=O)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CC(Cl)C(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A stirred solution of 152.6 g (0.74 mole) of 3-(4-methylbenzoyl)propionic methyl ester in 225 mL of methylene chloride was cooled to -5° C. in methanol:ice bath. A solution of 109.9 g (66 mL, 0.81 mole) of sulfuryl chloride (97%) in 65 mL of methylene chloride was added dropwise at a rate which maintained the temperature at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was cooled to 0° C. in an ice bath and treated with 3N sodium hydroxide until just basic. The organic portion was separated, dried over magnesium sulfate and concentrated in vacuo (172.9 g). The oil was distilled at 125° C. (150 mm Hg) in 4 fractions. A sample of fraction 2 was sent for elemental analysis.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[CH2:9]([N:17]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]=[C:18]1[CH:28]=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>CS(O)(=O)=O.C(Cl)(Cl)Cl>[CH3:8][N:5]1[CH2:6][CH2:7][CH:2]([O:1][CH:28]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH2:10][CH2:9][N:17]3[C:18]2=[N:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:21]3)[CH2:3][CH2:4]1
Reactant: CN1CCC(O)CC1
Reactant: O=Cc1nc(-c2ccccc2)cn1CCc1ccccc1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CN1CCC(OC2c3ccccc3CCn3cc(-c4ccccc4)nc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-hydroxy-N-methylpiperidine (275 mg, 2.39 mmoles) in methanesulfonic acid (2 mL) at 0° C. is added a solution of 1-phenethyl-4-phenyl-imidazole-2-carbaldehyde (example 4B) (250 mg, 0.904 mmoles) in chloroform (2 mL). The reaction mixture is stirred at room temperature overnight, then heated to reflux for 6 h. A saturated solution of Na2CO3 is added to reach pH 10. The aqueous phase is extracted three times with CH2Cl2. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using (CH2Cl2:MeOH) (90:10) to give 4-(1-methylpiperidin-4-yloxy)-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene melting at 113° C.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7][NH:8][CH3:9])=[CH:5][N:6]=1.CS[C:12](=[NH:17])[NH:13][N+:14]([O-:16])=[O:15]>C(O)C>[Cl:1][C:2]1[S:3][C:4]([CH2:7][N:8]([CH3:9])[C:12]([NH:13][N+:14]([O-:16])=[O:15])=[NH:17])=[CH:5][N:6]=1
Reactant: CNCc1cnc(Cl)s1
Reactant: CSC(=N)N[N+](=O)[O-]
Solvent: CCO
Product: CN(Cc1cnc(Cl)s1)C(=N)N[N+](=O)[O-]
Yield: 47.9 %

Procedure:
A mixture of 1.50 g of 2-chloro-N-methyl-5-thiazolemethanamine, 1.13 g of S-methyl-N-nitroisothiourea and 6 ml of ethanol was heated under reflux for 6 hours. After cooling, the reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (Solvent: Chloroform/Methanol=20/1) to obtain 1.00 g of the title compound as crystals. This compound is No. 6 in Table 1. m.p.: 116.0°-117.0° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:19]([O:21][CH3:22])=[O:20])[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:10]=2)=[CH:7][CH:8]=1.[C:23]([O-:26])(=[S:25])[CH3:24].[K+]>CC(C)=O>[C:23]([S:25][CH2:2][C:3]1[CH:4]=[C:5]([C:19]([O:21][CH3:22])=[O:20])[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:10]=2)=[CH:7][CH:8]=1)(=[O:26])[CH3:24]
Reactant: COC(=O)c1cccc(-c2ccc(CBr)cc2C(=O)OC)c1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(-c2ccc(CSC(C)=O)cc2C(=O)OC)c1
Temperature: 25 °C
Yield: 76.7 %

Procedure:
To a solution of 4-bromomethyl-[1,1′-biphenyl]-2,3′-dicarboxylic acid, dimethyl ester (1.59 g, 4.4 mmol) in acetone (75 mL) was added potassium thioacetate (0.60 g, 5.3 mmol), and the mixture was refluxed for 1 h. The mixture was allowed to cool to rt, filtered, and concentrated. The residual product was purified by column chromatography (hexanes/EtOAc, 9/1) to afford 4-acetylthiomethyl-[1,1′-biphenyl]-2,3′-dicarboxylic acid, dimethyl ester (1.21 g, 76%): 1H NMR (DMSO-d6) δ 2.39 (s, 3H), 3.60 (s, 3H), 3.88 (s, 3H), 4.23 (s, 2H), 7.42–7.44 (d, J=8.0 Hz, 1H), 7.57–7.60 (m, 3H), 7.74 (s, 1H), 7.83 (s, 1H), 7.96–7.99 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([CH3:18])[CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][N:21]1[C:25]([CH2:26]O)=[CH:24][C:23]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)=[N:22]1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[C:1]([O:5][C:6](=[O:19])[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([CH3:18])[CH:13]=[C:14]([O:17][CH2:26][C:25]3[N:21]([CH3:20])[N:22]=[C:23]([C:28]4[CH:29]=[CH:30][C:31]([O:34][C:35]([F:37])([F:36])[F:38])=[CH:32][CH:33]=4)[CH:24]=3)[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(O)cc2c1ccn2CC(=O)OC(C)(C)C
Reactant: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CO
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: Cc1cc(OCc2cc(-c3ccc(OC(F)(F)F)cc3)nn2C)cc2c1ccn2CC(=O)OC(C)(C)C

Procedure:
In analogy to the procedure described for example 3 c], (6-hydroxy-4-methyl-indol-1-yl)-acetic acid tert-butyl ester was reacted with [2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-methanol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give {4-methyl-6-[2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid tert-butyl ester as colorless liquid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[C:9](Cl)(=[O:11])[CH3:10]>C(OCC)(=O)C>[C:9]([O:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)Cl
Reactant: O=c1cc(O)cc[nH]1
Solvent: CCOC(C)=O
Product: CC(=O)Oc1cc[nH]c(=O)c1
Yield: 60 %

Procedure:
A 5.00 g quantity of 4-hydroxy-2-pyridone and 3.84 ml of acetyl chloride were reacted for 5 hours in the same manner as in Example 2. The title compound was isolated in an amount of 4.15 g from the reaction mixture in the same manner as in Example 2 except that ethyl acetate was used as extraction solvent. Yield was 60%.
Reaction SMILES: [NH2:1][C:2]1[C:11]2=[N:12][N:13]([CH2:21][CH2:22][CH3:23])[C:14]([CH2:15][C:16]([CH3:20])([CH3:19])[C:17]#[N:18])=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.C([OH:26])C.[OH-].[NH4+].OO>O>[NH2:1][C:2]1[C:11]2=[N:12][N:13]([CH2:21][CH2:22][CH3:23])[C:14]([CH2:15][C:16]([CH3:19])([CH3:20])[C:17]([NH2:18])=[O:26])=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCO
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)C#N
Agent: OO
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)C(N)=O
Temperature: 70 °C

Procedure:
3-(4-Amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-2,2-dimethylpropanenitrile (657 mg, 2.14 mmol), ethanol (10 mL), concentrated ammonium hydroxide (2.1 mL), and 30% w/w hydrogen peroxide (2.8 g) were combined in a sealed glass tube and heated at 70° C. for seven hours. During this time, the reaction was periodically cooled and the pressure released. Additional hydrogen peroxide (1.4 g) was added, and the reaction was heated at 70° C. for five hours, with periodic cooling and venting. The reaction was cooled to 0° C., and water (25 mL) was added. A precipitate formed and was isolated by filtration, washed with water, purified by chromatography on a HORIZON HPFC instrument (40M cartridge), and recrystallized from acetonitrile. The crystals were dried on the vacuum filter funnel for two hours to provide 485 mg of 3-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-2,2-dimethylpropanamide as a white solid, mp 224-225° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([OH:23])[CH:19]=3)[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:24][C:25]([C@H:29]1[CH2:34][CH2:33][C@H:32](O)[CH2:31][CH2:30]1)([CH3:28])[CH2:26][CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[C:25]([C@@H:29]1[CH2:30][CH2:31][C@H:32]([O:23][C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([CH2:12][N:9]2[CH2:10][CH2:11][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8]2)[CH:22]=[CH:21]3)[CH2:33][CH2:34]1)([CH2:26][CH3:27])([CH3:24])[CH3:28]
Reactant: CCOC(=O)C1CCN(Cc2ccc3cc(O)ccc3c2)CC1
Reactant: CCC(C)(C)[C@H]1CC[C@H](O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(Cc2ccc3cc(O[C@H]4CC[C@@H](C(C)(C)CC)CC4)ccc3c2)CC1
Reaction time: 0.33 h
Yield: 100.7 %

Procedure:
A mixture of 1-(6-hydroxy-naphthalen-2-ylmethyl)-piperidine-4-carboxylic acid ethyl ester (0.400 g, 1.28 mmol), trans-4-(1,1-dimethyl-propyl)-cyclohexanol (0.2395 g, 1.406 mmol) and triphenylphosphine (0.6695 g, 2.553 mmol) in toluene (5 mL, 40 mmol) was stirred for 20 min, then, diisopropyl azodicarboxylate (0.32 mL, 1.5 mmol) was added drop wise at 0° C. The solution was stirred at reflux overnight. The reaction was added to silica gel and the solvent was concentrated. The residue was purified with silica gel eluted with EtOAc in hexanes from 0 to 20% to give product as oil (0.6 g, 100%). LCMS: Rt=1.95 min, m/z=466.49 [M+H].
Reaction SMILES: C(O[C:4](=[O:30])[CH2:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH:10]([C:24]2[N:25]=[N:26][N:27]([CH3:29])[N:28]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:33]O.Cl>CO.O>[CH3:29][N:27]1[N:26]=[N:25][C:24]([CH:10]2[CH2:9][CH:8]([C:6]3[O:7][NH:33][C:4](=[O:30])[CH:5]=3)[CH2:13][CH2:12][N:11]2[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[N:28]1
Reactant: CCOC(=O)CC(=O)C1CCN(C(=O)OCc2ccccc2)C(c2nnn(C)n2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1nnc(C2CC(c3cc(=O)[nH]o3)CCN2C(=O)OCc2ccccc2)n1
Temperature: -40 °C
Reaction time: 0.67 h
Yield: 70.9 %

Procedure:
Benzyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-methyl-2H-tetrazol-5-yl)piperidine-1-carboxylate (0.499 g, 1.20 mmol) was dissolved in MeOH (6 mL) and cooled to −40° C. 3.8 M NaOH (0.316 mL, 1.20 mmol) dissolved in water (0.6 mL) was added and the reaction stirred at −40° C. for 40 min. Hydroxylamine (50% by weight in water, 0.074 mL, 1.20 mmol) was added and stirring continued for 3.5 h at −40° C. The reaction mixture was then added to a preheated 80° C. solution of 6 M HCl (6.01 mL, 36.03 mmol) and stirred for 20 min. The reaction mixture was partitioned between water and DCM. The aqueous phase was extracted twice with DCM and the combined organic phase was dried and evaporated. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 15-55% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Benzyl 2-(2-methyl-2H-tetrazol-5-yl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (327 mg, 71%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.96-2.15 (m, 2H), 2.41 (dt, 1H), 2.64-2.74 (m, 1H), 3.12-3.19 (m, 1H), 3.61-3.72 (m, 1H), 4.07-4.20 (m, 4H), 5.13 (s, 2H), 5.43 (s, 1H), 5.58-5.64 (m, 1H), 7.25-7.41 (m, 5H). MS m/z 385 (M+H)+
Reaction SMILES: Cl[C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]=[O:17])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[CH2:18]([O:25][CH2:26][CH2:27][OH:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl.CCCCCC>[CH2:18]([O:25][CH2:26][CH2:27][O:28][C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]=[O:17])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1c2ccccc2c(Cl)c2ccccc12
Reactant: OCCOCc1ccccc1
Solvent: ClCCl
Solvent: CCCCCC
Product: O=Cc1c2ccccc2c(OCCOCc2ccccc2)c2ccccc12
Yield: 29.5 %

Procedure:
Using the procedure outlined in Example 2A, 10-chloroanthracene-9-carbaldehyde (Aldrich) and 2-benzyloxyethanol (Aldrich) gave a 29.5% yield of 10-[2-(benzyloxy)ethoxy]anthracene-9-carbaldehyde, mp 68°-69°, (C,H), (CH2Cl2 /hexane).