Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[N:18]([CH2:19][CH2:20][CH2:21][CH:22]=O)[C:17]([CH2:24][CH2:25][CH3:26])=[N:16][C:11]=3[CH:12]=[N:13][C:14]=2[CH:15]=1>C(O)C>[CH3:3][O:2][N:4]=[CH:22][CH2:21][CH2:20][CH2:19][N:18]1[C:10]2[C:9]3[CH:8]=[CH:7][C:6]([Br:5])=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:16]=[C:17]1[CH2:24][CH2:25][CH3:26]
Reactant: CCCc1nc2cnc3cc(Br)ccc3c2n1CCCC=O
Reactant: CON
Agent: Cl
Solvent: CCO
Product: CCCc1nc2cnc3cc(Br)ccc3c2n1CCCC=NOC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methoxylamine hydrochloride (11.86 g, 142.1 mmol) was added to a solution of 4-(7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyraldehyde (25.6 g, 71.0 mmol, prepared as described in Example 17 Parts A through D) in ethanol (200 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was dissolved in water, neutralized with saturated sodium bicarbonate, and then extracted into dichloromethane. The extract was washed sequentially with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and then concentrated under reduced pressure to provide 27.1 g of 4-(7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyraldehyde O-methyloxime.
Reaction SMILES: [NH2:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:10][C:11]3[N:15]([CH3:16])[N:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12.S1C2C=CC=CC=2N=C1S[C:32](=[O:41])[C:33]([C:35]1[N:36]=[C:37]([NH2:40])[S:38][CH:39]=1)=[O:34].C(O)C>ClCCl>[NH2:40][C:37]1[S:38][CH:39]=[C:35]([C:33](=[O:34])[C:32]([NH:1][CH:2]2[C:20](=[O:21])[N:4]3[CH:3]2[S:8][CH2:7][C:6]([CH2:9][S:10][C:11]2[N:15]([CH3:16])[N:14]=[N:13][N:12]=2)=[C:5]3[C:17]([OH:19])=[O:18])=[O:41])[N:36]=1
Reactant: Nc1nc(C(=O)C(=O)Sc2nc3ccccc3s2)cs1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Solvent: CCO
Solvent: ClCCl
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=O)c3csc(N)n3)C2SC1
Reaction time: 0.25 h

Procedure:
3.29 g of 7-amino-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]ceph-3-em-4-carboxylic acid are suspended in 25 ml of dichloromethane and mixed with 2.7 ml of N,O-bis-(trimethylsilyl)acetamide. After 15 minutes, a clear solution is present. This is cooled to -15°, and 3.9 g of 2-(2-aminothiazol-4-yl)-2-oxothioacetic-acid-S-benzothiazol-2-ylester are added. After stirring for four hours at -15°, the preparation is stirred into 100 ml of ethanol, whereby the end product precipitates. This is stirred for one hour at 0°, filtered, washed with ethanol and vacuum dried. Yield: 3.9 g, i.e. 80.7%. M.p.: from 145° (decomp.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[OH-].[Na+]>O>[CH2:16]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10](=[O:12])[CH3:11])=[CH:6][CH:7]=1)[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCBr
Reactant: CC(=O)CCc1ccc(O)cc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCOc1ccc(CCC(C)=O)cc1
Yield: 90.1 %

Procedure:
4-(4-Hydroxyphenyl)-2-butanone (49 g) was added by portions while warming to a stirred solution of potassium hydroxide (0.33 m) in 15 ml of water. To this was added dropwise, 49.8 g of 1-bromopentane and the resultant mixture was stirred at reflux temperature overnight. The mixture was allowed to cool after which 500 ml of 20% sodium hydroxide was added and the resultant mixture was stirred an additional 30 minutes followed by extraction with ethylacetate. The organic extracts were dried and evaporated to yield approximately 63 g of the desired 4-(4-pentoxyphenyl)-2-butanone which was used to prepare the title compound as follows.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][NH:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:25]1[N:30]2[N:31]=[C:32]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[Cl:47])[C:33]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)=[C:29]2[N:28]=[C:27]([CH3:48])[N:26]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[C:25]1[N:30]2[N:31]=[C:32]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[Cl:47])[C:33]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)=[C:29]2[N:28]=[C:27]([CH3:48])[N:26]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2
Reactant: Cc1nc(Cl)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Reaction time: 8 h

Procedure:
To a mixture of 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (78 mg, 0.40 mmol) and diisopropylethylamine (0.094 ml, 0.52 mmol) in methylene chloride (2.5 ml) was added 4-chloro-7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo[1,5-a][1,3,5]triazine (I-2A-1b; 135 mg, 0.35 mmol), portionwise. After stirring overnight, the reaction was concentrated, in vacuo, to ½ volume and then purified on a Biotage™ Flash 12M column using 0-3% ethyl acetate in methylene chloride to afford 8A-1 (200 mg, quantitative) as a solid: +APcI MS (M+1) 551.2; 1H NMR (400 MHz, CD3OD) δ 7.50-7.34 (m, 4H), 7.32 (d, J=8.3 Hz, 2H), 7.21 (d, J=8.3 Hz, 2H), 4.60 (br s, 1H), 2.46 (s, 3H), 2.10-1.99 (br m, 2H), 1.50-1.40 (m, 9H).
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:10]=[CH:9][N:8]([CH2:11][C:12]2[O:16][C:15]([C:17](=[O:19])[CH3:18])=[CH:14][CH:13]=2)[N:7]=1)([O-:5])=[O:4].[CH2:20](O)[CH2:21][OH:22].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CC(=O)OCC.O>[CH3:18][C:17]1([C:15]2[O:16][C:12]([CH2:11][N:8]3[CH:9]=[CH:10][C:6]([N+:3]([O-:5])=[O:4])=[N:7]3)=[CH:13][CH:14]=2)[O:22][CH2:21][CH2:20][O:19]1
Reactant: CC(=O)c1ccc(Cn2ccc([N+](=O)[O-])n2)o1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#N
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC1(c2ccc(Cn3ccc([N+](=O)[O-])n3)o2)OCCO1
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and a Dean-Stark apparatus under inert atmosphere (N2), a solution of 1-[5-(3-nitro-pyrazol-1-ylmethyl)-furan-2-yl]-ethanone (1.760 g, 7.48 mmol), ethylene glycol (4.18 mL, 74.98 mmol) and TsOH (14 mg, 0.08 mmol) in toluene (74.8 mL) was heated to reflux for 4 h. The reaction mixture was allowed to cool to rt. Water (125 mL) and EA (25 mL) were added and the aq. phase was extracted with EA (2×50 mL). The combined org. extracts were washed with sat. aq. NaHCO3, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (60:40 hept-EA) gave the title compound as a yellow oil. TLC: rf (60:40 hept-EA)=022. LC-MS-conditions 02: tR=0.92 min; [M+H]+=280.04. 1H NMR (400 MHz, CDCl3) δ 1.71 (s, 3H), 3.95-4.02 (m, 2H), 4.02-4.09 (m, 2H), 5.36 (s, 2H), 6.33 (d, J=3.3 Hz, 1H), 6.41 (d, J=3.0 Hz, 1H), 6.91 (d, J=2.5 Hz, 1H), 7.48 (d, J=2.3 Hz, 1H).
Reaction SMILES: FC1C=CC=CC=1CC=O.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=[CH:19][CH:20]([CH:24]([CH3:26])[CH3:25])[C:21]([OH:23])=[O:22].[O:27]([C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37]O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=[CH:19][CH:20]([CH:24]([CH3:26])[CH3:25])[C:21]([O:23][CH2:37][C:36]1[CH:39]=[CH:40][CH:41]=[C:34]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:35]=1)=[O:22]
Reactant: OCc1cccc(Oc2ccccc2)c1
Reactant: CC(C)C(C=Cc1ccccc1F)C(=O)O
Agent: O=CCc1ccccc1F
Product: CC(C)C(C=Cc1ccccc1F)C(=O)OCc1cccc(Oc2ccccc2)c1

Procedure:
2-Fluorophenylacetaldehyde is converted into ethyl 4-(2-fluorophenyl)-4-isopropyl-3-butanoate and hydrolyzed to the acid using the procedure of Example 9. The acid, 4-(2-fluorophenyl)-2-isopropyl-3-butenoic acid, is reacted, via the acid chloride, with m-phenoxybenzyl alcohol to yield m-phenoxybenzyl 4-(2-fluorophenyl)-2-isopropyl-3-butenoate, MS m/e 404.3 (M+). 2-Fluorophenylacetaldehyde is prepared from o-fluoro-β-methoxystyrene via the dimethylacetal using the procedure of Winterfeldt, Berichte 96(12), 3349 (1963).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OC(C(F)(F)F)=O.[NH:21]1[CH2:24][CH:23]([NH:25][C:26]([CH2:28][NH:29][C:30](=[O:41])[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)=[O:27])[CH2:22]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([N:21]3[CH2:24][CH:23]([NH:25][C:26]([CH2:28][NH:29][C:30](=[O:41])[C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:38])[F:39])[CH:32]=4)=[O:27])[CH2:22]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3ccccc3)CC2)C1

Procedure:
A solution of 4-phenyl-cyclohexanone (Aldrich, 1.5 g, 8.62 mmol) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide TFA salt (as prepared in the previous step, 3.89 g, 12.9 mmol) in DCM (20 mL) was treated with TEA (6 mL, 43 mmol) for 10 min followed by NaBH(OAc)3 (Aldrich, 3.65 g, 17.2 mmol) for another 4 hours at room temperature. The reaction was quenched with saturated sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted 3 times with a chloroform/IPA “cocktail” (˜3:1, v/v). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was then purified by a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the two title compounds as white solids.
Reaction SMILES: C1(N(C2CCCCC2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([NH:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:17])=[O:16])=[CH:13][N:14]=2)CCCCC1.[CH:30]1([NH:36][C@H:37]2[CH2:42][CH2:41][C@H:40]([CH3:43])[CH2:39][CH2:38]2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.[CH3:44]OC(=O)CN(S(C1SC(N)=NC=1)(=O)=O)C>>[CH:30]1([N:36]([C@H:37]2[CH2:38][CH2:39][C@H:40]([CH3:43])[CH2:41][CH2:42]2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([N:18]([CH2:19][C:20]([OH:22])=[O:21])[CH3:44])(=[O:17])=[O:16])=[CH:13][N:14]=2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: C[C@H]1CC[C@H](NC2CCCCC2)CC1
Reactant: O=C(O)CNS(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: COC(=O)CN(C)S(=O)(=O)c1cnc(N)s1
Product: CN(CC(=O)O)S(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](C)CC2)s1

Procedure:
Prepared in a similar manner to [2-(3,3-dicyclohexyl-ureido)-thiazole-5-sulfonylamino]-acetic acid via cyclohexyl-(trans-4-methyl-cyclohexyl)-amine and [(2-amino-thiazole-5-sulfonyl)-methyl-amino]-acetic acid methyl ester to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[CH2:10][C:11]1([CH2:17][CH2:18][OH:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.C(N(CC)C(C)C)(C)C>ClCCl>[CH2:1]([O:8][C:9](=[O:20])[CH2:10][C:11]1([CH2:17][CH:18]=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CC1(CCO)CCCCC1)OCc1ccccc1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=CCC1(CC(=O)OCc2ccccc2)CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 9.1 %

Procedure:
A mixture of [1-(2-hydroxy-ethyl)-cyclohexyl]-acetic acid benzyl ester (1.3 g, 47 mmol), dimethyl sulfoxide (0.83 mL, 12 mmol), and N,N-diisopropylethylamine (2.0 mL, 12 mmol) in dichloromethane (20 mL) was cooled to 0° C. and sulfur trioxide-pyridine complex (1.9 g, 12 mmol) was added. The reaction mixture was stirred at 0° C. for 2 h and the reaction was quenched with 0.1 N HCl. The aqueous layer was discarded. The organic extract was washed twice with 0.1 N HCl and brine. The organic extract was dried with sodium sulfate, filtered, and concentrated to dryness to provide the title compound (1.17 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C@@:12]([CH2:18][CH2:19][O:20][Si](C(C)(C)C)(C)C)([C:14]([O:16]C)=O)[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCOC(C)=O>CCCCCCC>[O:16]=[C:14]1[C@:12]2([CH:11]=[CH:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13]2)[CH2:18][CH2:19][O:20]1
Reactant: COC(=O)[C@@]1(CCO[Si](C)(C)C(C)(C)C)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)N[C@@H]1C=C[C@@]2(CCOC2=O)C1
Temperature: 19 °C
Reaction time: 1 h

Procedure:
A 12-L three-neck round bottom flask with overhead mechanical stirrer, 2-L addition funnel and nitrogen inlet was charged the product of Example 1, Step A (1149 g, 2.875 mol, 1 eq) and THF (5.75 L). The addition funnel was charged with TBAF (1M solution in THF, 2.875 L, 2.875 mol, 1 eq) and this solution was added dropwise over ˜1 h. The temperature increased from 17 to 21° C. and the reaction was clear orange at the end. The reaction was stirred for 1 h at rt, when it was judged complete by TLC and HPLC. The reaction was poured into a 22-L separatory flask charged with EtOAc (4 L) and the organic layer was washed with brine (2 L). The organic layer was washed with additional brine (3×2 L) and these aqueous fractions were discarded. Heptane (4 L) was added and the organic layer was washed with water (3×2 L), brine (2×2 L) and the clear organic layer was checked by NMR for removal of n-Bu4NX. The organic layer was evaporated at 45° C. to about 750 mL, when the solution became hazy, heptane (800 mL) was added and instant crystallization of a white solid resulted. More heptane (300 mL) was added and the mixture was swirled at 40° C. for 10 min on the rotovap bath. Ice was added to bath and the suspension was stirred at 13° C. for 10 min. The solid was filtered on a Buchner funnel, washed with heptane (3×100 mL) and provided the product of Step A. 1H NMR (CHLOROFORM-d) δ: 6.02 (dd, J=5.4, 2.4 Hz, 1H), 5.77 (d, J=5.4 Hz, 1H), 5.21 (d, J=9.0 Hz, 1H), 4.91 (t, J=8.7 Hz, 1H), 4.37 (dd, J=7.5, 6.5 Hz, 2H), 2.21-2.39 (m, 3H), 2.07 (dd, J=13.8, 2.6 Hz, 1H), 1.44 (s, 9H). Calculated for C13H19NO4: 276.1 (M+23). found: 276.1.
Reaction SMILES: [C:1]([C@@H:5]1[C@@H:16]2[C:17]3[C:8](=[CH:9][C:10]([O:26][CH3:27])=[C:11]([O:24][CH3:25])[C:12]=3[CH2:13][C@@H:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15]2)[C:7](O)=[CH:6]1)([O:3][CH3:4])=[O:2].Cl.[H][H]>CO.C(OCC)(=O)C.[Pd]>[C:1]([C@H:5]1[C@@H:16]2[C:17]3[C:8](=[CH:9][C:10]([O:26][CH3:27])=[C:11]([O:24][CH3:25])[C:12]=3[CH2:13][C@@H:14]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:15]2)[CH2:7][CH2:6]1)([O:3][CH3:4])=[O:2]
Reactant: [H][H]
Reactant: COC(=O)[C@H]1C=C(O)c2cc(OC)c(OC)c3c2[C@@H]1C[C@H](c1ccccc1)C3
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@@H]1CCc2cc(OC)c(OC)c3c2[C@@H]1C[C@H](c1ccccc1)C3

Procedure:
To a solution of 0.5 g (1.3 mmol) of [1 R,8 S,9a R]-1-carbomethoxy-5,6-dimethoxy-3-hydroxy-8-phenyl-7,8,9,9a-tetrahydrophenalene (182-3A) in 50 mL of methanol, 50 mL of ethyl acetate, and 0.1 mL of concentrated aqueous hydrochloric acid was solution was added 0.2 g of 5% palladium supported on carbon and the mixture was shaken under 4 atmospheres of hydrogen until the gas uptake had ceased. The palladium catalyst was removed by filtration through Celite® filter aid and the filtrate concentrated to give a white solid, which was carried on to the next step without purification.
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[C:8]C=O.[CH3:12][O:13][CH:14](OC)[O:15][CH3:16]>>[CH3:12][O:13][CH:14]([O:15][CH3:16])[C:8]#[C:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:11])[CH3:1]
Reactant: COC(OC)OC
Reactant: CC(C)CCCCC#CC=O
Product: COC(C#CCCCCC(C)C)OC

Procedure:
One gm. (0.007 mole) of 8-methylnon-2-yn-1-al, 10 gm. (0.1 mole) of trimethylorthoformate and 0.2 g of para-toluene-sulfuric acid were distilled. Methyl formate and methyl alcohol were collected. The solution was diluted with 15 ml of water and extracted with ether. The ether solution was washed with 5% sodium bicarbonate, and then water. The ether extract was dried over sodium sulfate, concentrate and distilled under vacuum to give 1,1-dimethoxy-8-methyl-non-2-yne.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[C:9](Br)=[N:10][CH:11]=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[CH3:27][C:28]1[O:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[C:9]([C:31]2[O:32][C:28]([CH3:27])=[CH:29][CH:30]=2)=[N:10][CH:11]=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: Cc1ccc(B(O)O)o1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccnc1Br
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccnc1-c1ccc(C)o1

Procedure:
By carrying out the operation analogously to example 1, starting from 2-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation III, and 5-methyl-2-furanboronic acid, the desired product is obtained in the form of a white solid (yield=45%).
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:4]=1[CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH:36]1([O:41][C:42]2[CH:43]=[C:44]([CH:47]=[CH:48][C:49]=2[O:50][CH3:51])[CH:45]=O)[CH2:40][CH2:39][CH2:38][CH2:37]1>O1CCCC1>[CH:36]1([O:41][C:42]2[CH:43]=[C:44](/[CH:45]=[CH:5]/[C:4]3[C:25]([Cl:29])=[CH:26][CH:27]=[CH:28][C:3]=3[Cl:2])[CH:47]=[CH:48][C:49]=2[O:50][CH3:51])[CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: Clc1cccc(Cl)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(/C=C/c2c(Cl)cccc2Cl)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
A stirred suspension of 2,6-dichlorobenzyltriphenylphosphonium bromide (2.5 g) in dry tetrahydrofuran (30 mL) is treated dropwise with a solution of potassium t-butoxide (0.56 g) in dry tetrahydrofuran (32 mL) at 0° C. After stirring at this temperature for 1 hour, it is treated with a solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (1.1 g) in dry tetrahydrofuran (15 mL). The reaction mixture is stirred from 0° C. to 5° C. for 1.5 hours, and then allowed to warm to room temperature. After stirring overnight, the mixture is concentrated and the resulting residue is treated with ethyl acetate (200 mL). The resulting organic solution is filtered. The filtrate is concentrated and the resulting residue is subjected to flash chromatography, eluting with dichloromethane, to give trans-1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(2,6-dichlorophenyl)ethene (1.16 g), m.p. 47-49° C. [Elemental analysis: C, 66.4; H, 5.6; Cl, 19.4%. calculated: C, 66.1; H, 5.55; Cl, 19.5%].
Reaction SMILES: BrC1C=CC(OC)=C(C)C=1.C1(CCN2CCNCC2)C=CC=CC=1.[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][C:36](Br)=[CH:35][C:34]=1[F:40])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH:41]1([CH2:47][CH2:48][CH2:49][N:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>>[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][C:36]([N:53]2[CH2:54][CH2:55][N:50]([CH2:49][CH2:48][CH2:47][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)[CH2:51][CH2:52]2)=[CH:35][C:34]=1[F:40])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Fc1cc(Br)ccc1OCc1ccccc1
Reactant: C1CCC(CCCN2CCNCC2)CC1
Agent: COc1ccc(Br)cc1C
Agent: c1ccc(CCN2CCNCC2)cc1
Product: Fc1cc(N2CCN(CCCC3CCCCC3)CC2)ccc1OCc1ccccc1
Yield: 111.4 %

Procedure:
Production Example 9 was repeated except that 5-bromo-2-methoxytoluene and 1-(2-phenylethyl)piperazine were replaced with 1-benzyloxy-4-bromo-2-fluorobenzene (1.42 g) and 1-(3-cyclo-hexylpropyl)piperazine (1.28 g), respectively, to provide crude 1-(4-benzyloxy-3-fluorophenyl)-4-(3-cyclohexylpropyl)piperazine (2.31 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:24]([NH2:26])=[O:25])[C:5]2[NH:6][C:7]3[C:12]([C:13]=2[C:14]=1[F:15])=[CH:11][C:10]([C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17])=[CH:9][CH:8]=3.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>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.CO>[F:15][C:14]1[C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[O:17])[CH:11]=3)[NH:6][C:5]=2[C:4]([C:24]([NH2:26])=[O:25])=[CH:3][C:2]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NC(=O)c1cc(Br)c(F)c2c1[nH]c1ccc(C(=O)N3CCOCC3)cc12
Reactant: OB(O)c1ccccc1
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: Cc1ccccc1
Solvent: CO
Product: NC(=O)c1cc(-c2ccccc2)c(F)c2c1[nH]c1ccc(C(=O)N3CCOCC3)cc12
Temperature: 105 °C
Reaction time: 3 h
Yield: 39.4 %

Procedure:
3-Bromo-4-fluoro-6-(morpholine-4-carbonyl)-9H-carbazole-1-carboxamide (25 mg, 0.059 mmol), phenylboronic acid (10.88 mg, 0.089 mmol), Pd(Ph3P)4 (6.87 mg, 5.95 μmol) and Na2CO3(2M) (0.074 mL, 0.149 mmol) were mixed with toluene (2 mL) and MeOH (1 mL) in a sealed microwave tube. The mixture was stirred at 105° C. for 3 hrs. The mixture was filtered through a ACRODISC® PTFE membrane (0.45 um) and purified using preparative HPLC to give 9.7 mg of 4-fluoro-6-(morpholine-4-carbonyl)-3-phenyl-9H-carbazole-1-carboxamide. MS (ESI) m/z 418.06 (M+H)+. 1H NMR (DMSO-d6) δ ppm 11.9 (bs, 1H), 8.32 (bs, 1H), 8.19 (d, 1H, J=7.1), 8.15 (s, 1H), 7.84 (d, 1H, J=8.6), 7.72 (d, 2H, J=7.3), 7.62-7.53(m, 4H), 7.43 (t, 1H, J=7.3), 3.7-3.5 (bm, 8H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[N:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[N:33][CH:32]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCO.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>[N:31]1[CH:36]=[C:35]([C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9]([N:11]3[CH2:12][CH2:13][CH:14]([C:17]4[C:26]5[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=5)[N:20]=[CH:19][N:18]=4)[CH2:15][CH2:16]3)=[O:10])=[CH:6][CH:7]=2)[CH:34]=[N:33][CH:32]=1
Reactant: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(I)cc4)CC3)c2cc1OC
Reactant: OB(O)c1cncnc1
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(-c5cncnc5)cc4)CC3)c2cc1OC
Temperature: 100 °C
Yield: 35.6 %

Procedure:
To a suspension of 4-(6,7-dimethoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-iodo-phenyl)-amide (58.2 mg, 0.11 mmol), as prepared in Example 2b, in 1 mL of toluene/EtOH (4:1, v/v) were added pyrimidine-5-boronic acid (15.3 mg, 0.12 mmol), Pd(PPh3)4 (6.5 mg) and 2M K2CO3 solution (0.23 mL). The reaction mixture was heated at 100° C. overnight. It was concentrated under reduced pressure and the black residue was purified by flash column chromatography on silica gel (5% MeOH/EtOAc as eluent) to afford the desired product (18.4 mg, 35.6% yield). 1H NMR (300 MHz, CDCl3) δ 9.17 (s, 1H), 9.09 (s, 1H), 8.94 (s, 2H), 7.55 (s, 4H), 7.38 (s, 1H), 7.27 (s, 1H), 6.59 (s, 1H), 4.32 (m, 2H), 4.09 (s, 3H), 4.08 (s, 3H), 3.65 (m, 1H), 3.23 (m, 2H), 2.19 (m, 2H), 2.03 (m, 2H). LC-MS (ESI) calcd mass 470.2, found 471.3 (MH+).