Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[N:9]2[C:4]([O:5][CH2:6][CH2:7][CH2:8]2)=[CH:3][C:2]=1[C:10]([O-])=[O:11].[BH4-].[Li+].CO>C1COCC1>[NH:1]1[N:9]2[CH:4]([O:5][CH2:6][CH:7]=[CH:8]2)[CH2:3][CH:2]1[CH2:10][OH:11]
Reactant: O=C([O-])c1cc2n(n1)CCCO2
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: OCC1CC2OCC=CN2N1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 67 %

Procedure:
To the stirred solution of 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylate: (4.0 g, 20 mmol) of in 100 ml of THF was added 0.71 g of lithium borohydride and 1.03 g of methanol. The solution was heated at 40 C. for 2.5 hour. The reaction was quenched by 1N HCl, and adjusted to pH 1.3 and stirred at room temperature for 1 hour. The reaction mixture was adjusted pH to 8 with k2CO3. The reaction mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4, and concentrated to an oil and column chromatographyed to give 2.08 g of the desired product (67%); (M+H) 155.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].N1C=CC=CC=1.Cl[C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[C:18]([O:1][CH2:2][CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)CCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 5 °C
Reaction time: 20 h
Yield: 65.9 %

Procedure:
To a solution of tert-butyl 3-hydroxypropanoate (2 g, 13.68 mmol) in dry DCM (50 ml), pyridine (3.32 ml, 41.0 mmol) was added. The solution was cooled to 5° C., and (chloromethanetriyl)tribenzene (3.81 g, 13.68 mmol) was added portion-wise; the ice cooling was removed and stirring was continued for 20 hours. The solvent was evaporated and the residue was portioned between EtOAc and water; the organic layer was washed with a 3% aqueous solution of citric acid, with brine and dried over Na2SO4. The solvent was removed and the residue was purified by flash chromatography on silica gel column (petroleum ether:EtOAc=95:5) affording tert-butyl 3-(trityloxy)propanoate (3.5 g, 9.01 mmol, 65.8% yield, MS/ESI+ 411.3 [MNa]+).
Reaction SMILES: C[Li].C(NC(C)C)(C)C.[CH2:10]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=1)[CH:11]([CH3:13])[CH3:12].Cl[Si:28]([CH3:31])([CH3:30])[CH3:29]>C(OCC)C>[CH2:24]([O:23][C:21]([O:22][Si:28]([CH3:31])([CH3:30])[CH3:29])=[C:20]([CH3:26])[C:17]1[CH:16]=[CH:15][C:14]([CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:19][CH:18]=1)[CH3:25]
Reactant: C[Si](C)(C)Cl
Reactant: CCOC(=O)C(C)c1ccc(CC(C)C)cc1
Agent: [Li]C
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: CCOC(O[Si](C)(C)C)=C(C)c1ccc(CC(C)C)cc1
Temperature: -70 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
Methyllithium in diethyl ether (0.25 mol, 140 ml of 1.8 M solution) was added dropwise to a solution of 27.6 g (0.27 mol) of diisopropylamine in 40 ml of diethyl ether. The reaction mixture was cooled to -70° C. and 37.5 g (0.16 mol) of ethyl 4-isobutyl-α-methylphenylacetate were added dropwise. The reaction mixture was warmed to 0° C. and 46 ml (0.36 mol) of chlorotrimethylsilane were added. The reaction mixture was stirred overnight at 25° C., filtered and then distilled to give 34.3 g (70% yield) of β-ethoxy-4-isobutyl-α-methyl-β-(trimethylsiloxy)-styrene as a colorless liquid, bp 129°-130° C. (0.4 mm). Anal. Calcd. for C18H30O2Si: C, 70.53; H, 9.87; Found: C, 70.38; H, 9.78.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27]Cl)[CH2:21][CH2:20]1>>[O:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][O:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[O:5][C:4](=[O:12])[C:3]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:21][CH2:20]1
Reactant: CC(C)(CCl)CN1CCOCC1
Reactant: O=c1oc2ccccc2c(O)c1-c1ccccc1
Product: CC(C)(COc1c(-c2ccccc2)c(=O)oc2ccccc12)CN1CCOCC1
Yield: 87.2 %

Procedure:
Prepared according to the method of Example 8 from 4-hydroxy-3-phenyl-coumarin and 3-morpholino-2,2-dimethyl-1-chloropropane. By recrystallisation from ethanol, a solid melting at 167° C. is obtained. Yield 87.2%.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[S:20][CH:21]=[CH:22][N:23]=3)(=[O:17])=[O:16])=[CH:11][C:10]=2[C:24]#[N:25])=[C:4]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:3]=1.[F:32][C:33]1[N:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:24]([C:10]1[CH:11]=[C:12]([S:15]([NH:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)(=[O:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][C:5]1[C:4]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:3][C:2]([C:36]2[CH:37]=[N:38][C:33]([F:32])=[CH:34][CH:35]=2)=[N:7][CH:6]=1)#[N:25]
Reactant: OB(O)c1ccc(F)nc1
Reactant: N#Cc1cc(S(=O)(=O)Nc2nccs2)ccc1Oc1cnc(Cl)cc1-c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(S(=O)(=O)Nc2nccs2)ccc1Oc1cnc(-c2ccc(F)nc2)cc1-c1cccnc1
Reaction time: 0.17 h
Yield: 28.3 %

Procedure:
10 mg (0.02 mmol) of 4-((6′-chloro-[3,4′-bipyridin]-3′-yl)oxy)-3-cyano-N-(thiazol-2-yl)benzenesulfonamide was dissolved in 3 mL of N,N-dimethylformamide, and 4.5 mg (0.03 mmol) of (6-fluoropyridin-3-yl)boronic acid was added thereto, and then 2.4 mg (10 mol %) of Pd(PPh3)4, 6.7 mg (0.6 mmol) of Na2CO3, and 1 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 10 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 3 mg (27% yield) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23]([O:25]C)=O.Cl.[OH-].[NH4+:29]>C1COCC1.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23](=[O:25])[NH2:29]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1C
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccccc1Cn1c2cccc(O)c2c2c(C(N)=O)cccc21
Yield: 36 %

Procedure:
A solution of the 9-[(2-methylphenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (260 mg, 0.75 mM) in 10 mL THF and 30 mL concentrated aqueous ammonium hydroxide was sonicated for 5 hours at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with H2O and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient hexanes/ethyl acetate) to afford 90 mg (36%) of the 9-[(2-methylphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a tan solid. 1H NMR (DMSO-d6) δ 10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.7 (m, 1H), 7.5 (m, 2H), 7.3 (m, 2H), 7.1 (t, 1H, J=8 Hz), 6.95 (d, 1H, J=8 Hz), 6.85 (t, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 5.95 (d, 1H, J=8 Hz), 5.7 (s, 2H), and 2.5 (s, 3H). IR (KBr, cm−1) 3451, 3191, 1627, 1600, 1584, 1562, 1435, 1329, 1322, 1263, and 774. MS (ES) m/e 329, 331.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:30]([CH3:31])=[CH:29][C:15]2[N:16]=[C:17](C3C=CC4N(C)N=NC=4C=3)[S:18][C:14]=2[C:13]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:39][C:40]1[N:41]=[C:42]([CH3:58])[N:43]2[CH:48]=[CH:47][C:46](B3OC(C)(C)C(C)(C)O3)=[CH:45][C:44]=12>>[C:1]([O:5][C@@H:6]([C:12]1[C:30]([CH3:31])=[CH:29][C:15]2[N:16]=[C:17]([C:46]3[CH:47]=[CH:48][N:43]4[C:42]([CH3:58])=[N:41][C:40]([CH3:39])=[C:44]4[CH:45]=3)[S:18][C:14]=2[C:13]=1[C:32]1[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1nc(C)n2ccc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)nnn4C)sc2c1-c1ccc(Cl)cc1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccn4c(C)nc(C)c4c3)sc2c1-c1ccc(Cl)cc1

Procedure:
Prepared in manner similar to (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)benzo[d]thiazol-6-yl)acetate, but using 1,3-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,5-a]pyridine instead of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d][1,2,3]triazole. 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.82 (s, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.51 (dt, J=14.3, 7.8 Hz, 5H), 5.15 (s, 1H), 4.21 (dd, J=5.9, 3.5 Hz, 2H), 2.67 (s, 3H), 2.59 (s, 3H), 2.54 (s, 3H), 1.25 (t, J=6.0 Hz, 3H), 0.98 (s, 9H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:7]2[C:6]([C:4]3[N:3]=[CH:2][N:1]([C:24]4[CH:23]=[CH:22][CH:21]=[C:20]([F:19])[CH:25]=4)[CH:5]=3)=[C:10]([CH3:11])[O:9][N:8]=2)=[CH:13][CH:14]=1
Reactant: Cc1onc(-c2ccc(F)cc2)c1-c1c[nH]cn1
Reactant: OB(O)c1cccc(F)c1
Product: Cc1onc(-c2ccc(F)cc2)c1-c1cn(-c2cccc(F)c2)cn1
Yield: 12 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-(4-fluorophenyl)-isoxazole (73 mg, 0.3 mmol) was converted, using 3-fluorophenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (13 mg, 12%) which was obtained as an off-white solid. MS: m/e=338.3 [M+H]+.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:6]=2[CH:5]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:3]=1.C[O:27][B:28](OC)[O:29]C>>[Cl:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][N:7]1[C:6]2[CH:5]=[C:4]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:3]=[C:2]([B:28]([OH:29])[OH:27])[C:10]=2[N:9]=[C:8]1[CH3:11]
Reactant: Cc1nc2c(Br)cc(N3CCOCC3)cc2n1Cc1cccc(Cl)c1
Reactant: COB(OC)OC
Product: Cc1nc2c(B(O)O)cc(N3CCOCC3)cc2n1Cc1cccc(Cl)c1

Procedure:
The titled compound was prepared from 4-(4-bromo-1-(3-chlorobenzyl)-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine (0.65 g, 1.545 mmol) using Method A with trimethylborate to give the product (109 mg, 17%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.82 (s, 3H) 3.22 (m, 4H) 3.78 (m, 4H) 5.69 (s, 2H) 7.19 (m, 1H) 7.33-7.48 (m, 4H) 7.78 (s, 1H); MS (ES+) 386.0 m/z.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH3:5][C:6]1[CH:7]=[C:8]2[N:13]([C:14]=1[C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][CH:10]=[CH:9]2>O.C(O)(=O)C>[CH3:5][C:6]1[C:7]([N:1]=[O:3])=[C:8]2[N:13]([C:14]=1[C:15]([O:17][CH3:18])=[O:16])[CH:12]=[CH:11][CH:10]=[CH:9]2
Reactant: COC(=O)c1c(C)cc2ccccn12
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1c(C)c(N=O)c2ccccn12
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
A solution of sodium nitrite (2.2 g, 31.90 mmol) in water (10 mL) was added slowly at 0-5° C. to a stirred solution of methyl 2-methylindolizine-3-carboxylate 2 (3.9 g, 20.61 mmol) in glacial acetic acid (50 mL). After 30 min, the brown reaction mixture was poured into water. Green crystals were collected by filtration, washed with water and then dried under vacuum to give 3.7 g of expected compound; m.p.: 131-132° C. 1H NMR (CDCl3): 9.63 (d, J=7.0 Hz, 1H), 8.39 (d, J=8.5 Hz, 1H), 7.74-7.69 (m, 1H), 7.23-7.18 (m, 1H), 4.03 (s, 3H), 3.26 (s, 3H), 13C NMR (CDCl3): δ 162.5, 154.5, 141.7, 135.7, 127.9, 123.2, 118.4, 118.3, 114.5, 51.7, 11.1. Analysis calculated for C11H10N2O3: C, 60.55; H, 5.54; N, 12.84, found: C, 60.65; H, 5.60; N, 12.90.
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cu])=[CH:7][CH:6]=1.Br[CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[CH3:1][C:2]([CH3:12])=[CH:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][CH:6]=1
Reactant: CC(C)=CCc1ccc([Cu])cc1
Reactant: CCOC(=O)C(C)Br
Product: CCOC(=O)C(C)c1ccc(CC=C(C)C)cc1
Yield: 6.7 %

Procedure:
In the same way as in Comparative Example 7, p-(3-methyl-2-butenyl)phenyl copper (I) was reacted with ethyl α-bromopropionate. Ethyl α-[p-(3-methyl-2-butenyl)phenyl]propionate was obtained in an amount of 1.64 g (yield 6.7%).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[CH:17]=[C:18]([NH:24][C:25]2[N:30]=[C:29]([CH2:31][N:32]3[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]3)[CH:28]=[CH:27][CH:26]=2)[C:19]([C:22]#[N:23])=[N:20][CH:21]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[CH:17]=[C:18]([NH:24][C:25]2[CH:26]=[CH:27][CH:28]=[C:29]([CH2:31][N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[N:30]=2)[C:19]([C:22]#[N:23])=[N:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cnc(C#N)c(Nc2cccc(CN3CCN(C(=O)OC(C)(C)C)CC3)n2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ncc(N[C@@H]2CCCC[C@@H]2N)cc1Nc1cccc(CN2CCNCC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-[(6-{[5-({(1R,2S)-2-[(tert-butoxycarbonyl)amino]cyclohexyl}amino)-2-cyanopyridin-3-yl]amino}pyridin-2-yl)methyl]piperazine-1-carboxylate (90 mg, 0.15 mmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (0.17 mL, 2.2 mmol) and the reaction mixture was stirred for 1 hour at room temperature. The reaction was then concentrated under reduced pressure to afford 5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-{[6-(piperazin-1-ylmethyl)pyridin-2-yl]amino}pyridine-2-carbonitrile. The material was used in the next step without further purification. MS ESI calc'd for C22H31N8 [M+H]+ 407. found 407.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][C:3](=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:7]([O:9][CH3:10])=[O:8])[CH2:2]1.S(Cl)(Cl)(=O)=O>C1(C)C=CC=CC=1>[S:1]1[CH:5]=[CH:4][C:3](=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:7]([O:9][CH3:10])=[O:8])[CH2:2]1
Reactant: COC(=O)C(C(=O)OC)=C1CCSC1
Solvent: Cc1ccccc1
Solvent: O=S(=O)(Cl)Cl
Product: COC(=O)C(C(=O)OC)=C1C=CSC1
Reaction time: 0.25 h
Yield: 0.1 %

Procedure:
A solution of 0.50 g (2.31 mol) of dimethyl 2-(3-tetrahydrothienylidene)malonate in 10 ml of toluene was treated with 0.32 g (2.35 mmole) of sulfuryl chloride in 1 ml of toluene under nitrogen at ice bath temperature. The mixture turned dark, and starting material could not be observed by tlc after 5 min. Nitrogen was bubbled through the solution for 5 min., and the dark color faded. Pyridine (1 ml) was added. After 15 min. at room temperature, the solution was worked up as in Example 1 and molecular distillation gave 0.45 g (93%) of dimethyl 2-(3-thienylidene)malonate, containing minor impurities by glc (SE-30, 200° ).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]2[C:12]([C:17]([OH:19])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[N:7]([C:20]2[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:27])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:28][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>CC#N>[C:1]([C:5]1[C:9]([F:28])=[C:8]([NH:10][C:11]2[C:12]([C:17]([OH:19])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[N:7]([C:20]2[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:27])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: F[B-](F)(F)F
Reactant: Cc1cccc(C)c1-n1nc(C(C)(C)C)cc1Nc1cccnc1C(=O)O
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: Cc1cccc(C)c1-n1nc(C(C)(C)C)c(F)c1Nc1cccnc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
To a solution of 3-{[3-tert-butyl-1-(2,6-dimethylphenyl)-1H-pyrazol-5-yl]amino}pyridine-2-carboxylic acid (Example 10, 50 mg, 0.14 mmol) in CH3CN (1 mL) was added [(1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)] (SELECTFLUOR™) (48 mg, 0.14 mmol), and the mixture was stirred at rt for 16 h. The mixture was concentrated, and the residue was subjected to HPLC purification with a gradient elution from 10% to 90% acetonitrile in water to afford 22 mg (42%) of the title compound. 1H NMR (300 MHz, CD2Cl2) δ 9.18 (s, 1H), 8.04 (d, 1H), 7.50 (dd, 1H), 7.42 (m, 1H), 7.28 (m, 1H), 7.13 (m, 2H), 2.12 (s, 6H), 1.40 (s, 9H). ES-MS m/z 383.1 (MH+); HPLC RT (min) 3.21.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7](Br)=[CH:8][CH:9]=1)=[O:4].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([C:7]2[O:6][C:5]([C:3]([OH:2])=[O:4])=[CH:9][CH:8]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1ccc(Br)o1
Product: O=C(O)c1ccc(-c2ccccc2)o1

Procedure:
5-Bromo-furan-2-carboxylic acid methyl ester (5) (205 mg, 1 mmol) was coupled to phenylboronic acid (146 mg, 1.2 mmol) using Method E except that once the reaction was complete, the solvents were removed in vacuo. The crude residue was re-dissolved in EtOAc (10 ml) and 1M NaOH (20 ml) was added. The aqueous layer was extracted with EtOAc (3×10 ml), and the organic layer was discarded. The aqueous layer was acidified to pH 1 with conc. HCl, and extracted with EtOAc (3×10 ml). The combined organic layers were dried (MgSO4), filtered, and the solvent removed in vacuo to give the title compound.
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:22][C:23]1[CH:47]=[CH:46][C:26]([CH2:27][N:28]2[C:36]3[C:31](=[CH:32][C:33]([O:37][CH3:38])=[CH:34][CH:35]=3)[C:30]([C:39]3([CH2:42][CH2:43]O)[CH2:41][CH2:40]3)=[C:29]2[CH3:45])=[CH:25][CH:24]=1>C(Cl)Cl>[Br:22][C:23]1[CH:47]=[CH:46][C:26]([CH2:27][N:28]2[C:36]3[C:31](=[CH:32][C:33]([O:37][CH3:38])=[CH:34][CH:35]=3)[C:30]([C:39]3([CH2:42][CH2:43][Br:1])[CH2:41][CH2:40]3)=[C:29]2[CH3:45])=[CH:25][CH:24]=1
Reactant: BrBr
Reactant: COc1ccc2c(c1)c(C1(CCO)CC1)c(C)n2Cc1ccc(Br)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc2c(c1)c(C1(CCBr)CC1)c(C)n2Cc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.2 %

Procedure:
Bromine (136 mg, 0.85 mmol) was added to a-78° C. solution of triphenylphosphine (244 rag, 0.93 mmol) in 4 mL CH2Cl2, and the mixture was stirred 0.5 h at 0° C. and 5 rain at r.t. before recooling to -5° C. The alcohol from Step 8 (319 mg, 0.77 mmol) was then slowly added as a 1 mL CH2Cl2 solution and the mixture was stirred 2 h at 0° C. The reaction mixture was partitioned between CH2Cl2 and saturated NaHCO3. The organic layer was dried over MgSO4, concentrated and the residue purified by flash chromatography (10% ethyl acetate in hexane) to give 166 mg of the title compound.
Reaction SMILES: C([O:4][CH2:5][C:6]([N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:12]([C:21](=[O:23])[NH2:22])[CH:11]=[N:10]1)([CH3:8])[CH3:7])(=O)C.[OH-].[Na+].O.Cl>CO>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[N:9]([C:6]([CH3:8])([CH3:7])[CH2:5][OH:4])[N:10]=[CH:11][C:12]=2[C:21]([NH2:22])=[O:23])=[CH:15][CH:16]=1
Reactant: CC(=O)OCC(C)(C)n1ncc(C(N)=O)c1-c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(CO)n1ncc(C(N)=O)c1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of the compound (95 mg, 0.30 mmol) obtained in step 1 in methanol (3 mL) was added 6N aqueous sodium hydroxide solution (0.05 mL), and the mixture was stirred at 60° C. for 1 hr. To the reaction mixture were added water and 6M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure to give 5-(4-fluorophenyl)-1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazole-4-carboxamide (60 mg, 0.216 mmol, 73%) as a white powder.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]1([F:35])[O:34][C:16]2=[CH:17][C:18]3[NH:22][C:21]([S:23][CH2:24][C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][N:26]=4)=[N:20][C:19]=3[CH:33]=[C:15]2[O:14]1.C(N(CC)CC)C.C(=O)(O)[O-].[K+]>C(Cl)Cl>[F:35][C:13]1([F:12])[O:34][C:16]2=[CH:17][C:18]3[NH:22][C:21]([S:23]([CH2:24][C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][N:26]=4)=[O:6])=[N:20][C:19]=3[CH:33]=[C:15]2[O:14]1
Reactant: COc1ccnc(CSc2nc3cc4c(cc3[nH]2)OC(F)(F)O4)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccnc(CS(=O)c2nc3cc4c(cc3[nH]2)OC(F)(F)O4)c1
Yield: 76.5 %

Procedure:
A solution of 0.91 g of approximately 85% pure m-chloroperoxybenzoic acid in 20 ml of methylene chloride is added dropwise to a solution of 1.5 g of 2,2-difluoro-6-[(4-methoxy-2-pyridyl)methylthio]-5H-[1,3]-dioxolo[4,5-f]benzimidazole in 50 ml of methylene chloride at -30° C. in the course of 5 min., with stirring, and the temperature is allowed to rise to -10° C. in the course of 30 min. 0.62 ml of triethylamine is added, followed by 20 ml of aqueous potassium bicarbonate solution, the title compound already crystallizing out in the cold. The mixture is filtered and the precipitate is washed with water to yield 1.2 g of the title compound. The organic phase is separated off from the filtrate, washed with water and dried with magnesium sulfate and the solution is concentrated completely, at 30° C. A further 0.25 g of the title compound is obtained from the residue by recrystallization from ethyl acetate; total yield: 92%, m.p.: 184°-185° C. (decompositon).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]([O:9][C:10](=O)[O:11]C(C)(C)C)([CH3:8])([CH3:7])[CH3:6].[OH-].[Na+]>O1CCOCC1>[C:10]([NH:4][CH2:3][CH2:1][OH:2])([O:9][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:11]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: NCCO
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of ethanolamine (0.1 mol), di-tert-butylcarbonate (0.15 mol), dioxane (50 mL) and aq. 2 N NaOH (25 mL) is stirred at RT for 24 hr. The dioxane is removed by evaporation under reduced pressure. Water (50 mL) is added to the aqueous mixture and the mixture is extracted with CH2Cl2 (4×25 mL). The combined organic layers are dried (Na2SO4), filtered and concentrated under reduced pressure to give the crude product. Pure N-BOC-ethanolamine is obtained by purification of the crude product with the use of flash chromatography over silica gel.