Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[N:14]=[C:13]([C:15]2[N:19](COCC[Si](C)(C)C)[C:18]([C:28]3[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=3[CH3:35])=[C:17]([C:36]([NH2:38])=[O:37])[CH:16]=2)[C:12]([C:39]#[C:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]([N:49]3[CH2:54][CH2:53][N:52]([CH3:55])[CH2:51][CH2:50]3)=[O:48])=[CH:43][CH:42]=2)=[CH:11][N:10]=1>C(Cl)Cl>[NH2:8][C:9]1[N:14]=[C:13]([C:15]2[NH:19][C:18]([C:28]3[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=3[CH3:35])=[C:17]([C:36]([NH2:38])=[O:37])[CH:16]=2)[C:12]([C:39]#[C:40][C:41]2[CH:42]=[CH:43][C:44]([C:47]([N:49]3[CH2:54][CH2:53][N:52]([CH3:55])[CH2:51][CH2:50]3)=[O:48])=[CH:45][CH:46]=2)=[CH:11][N:10]=1
Reactant: Cc1ccc(Cl)cc1-c1c(C(N)=O)cc(-c2nc(N)ncc2C#Cc2ccc(C(=O)N3CCN(C)CC3)cc2)n1COCC[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(Cl)cc1-c1[nH]c(-c2nc(N)ncc2C#Cc2ccc(C(=O)N3CCN(C)CC3)cc2)cc1C(N)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.9 %

Procedure:
Trifluoroacetic acid (1.4 mL) was added to a solution of 5-[2-amino-5-({4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}ethynyl)pyrimidin-4-yl]-2-(5-chloro-2-methylphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxamide (0.110 g, 0.14 mmol) in dry DCM (2.8 mL) and stirred for 4 h at room temperature. After solvent removal, the residue was treated with EtOH (3 mL), 33% NH4OH (0.4 mL) and stirred for 0.5 h. The solvent was evaporated to dryness and the residue was purified by flash-chromatography on silica gel (DCM/MeOH/7N NH3 in MeOH 94/5/1) to afford the title compound as white solid (0.055 g, 71%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:29]([OH:31])=O)=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:32]([O:39][CH2:40][CH2:41][NH:42][CH3:43])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].[Si](OCCN(C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2C=CC=CC=2C2C=CC=CC=2)N=1)=O)(C(C)(C)C)(C)C>>[Si:32]([O:39][CH2:40][CH2:41][N:42]([CH3:43])[C:29]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]=1)=[O:31])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:33])[CH3:34]
Reactant: CNCCO[Si](C)(C)C(C)(C)C
Reactant: O=C(O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Product: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Yield: 47.9 %

Procedure:
5-Benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]methyl-amide (29-02) (2 g, 47.85%) was synthesized from 5-benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (28-02) (3 g, 6.84 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amine (8-a) as a gummy solid (1.4 g, 7.53 mmol) following the procedure as described for 5-benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (9-01).
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].[CH3:7][CH:8]([CH3:11])[CH:9]=[O:10].Cl>>[OH:10][C@@H:9]([P:1](=[O:6])([O:4][CH3:5])[O:2][CH3:3])[CH:8]([CH3:11])[CH3:7]
Reactant: COP([O-])OC
Reactant: CC(C)C=O
Agent: Cl
Product: COP(=O)(OC)[C@H](O)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
The solution of ALB in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 1 was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added dimethyl phosphite (37 μl, 0.40 mmol) at room temperature. After stirring at room temperature for 30 minutes, the reaction vessel was cooled to -40° C., and it was maintained at this temperature for 15 minutes. Then 2-methylpropionaldehyde (0.40 mmol) was added thereto. After reacting for 38 hours, 1N hydrochloric acid was added thereto to stop the reaction. The mixture was extracted with ethyl acetate (10 ml×three times), and the combined extracts were washed with brine and dried over Na2SO4. The solvent was distilled, and the residue was purified by flash column chromatography (acetone/hexane=1/5, on SiO2) to obtain dimethyl (S)-1-hydroxy-2-methylpropylphosphonate as a final product in a yield of 95%. The chemical reaction in this Example is shown in chemical formula 41.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:35]=1)[O:7][CH2:8][C:9]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:10]=1/[C:11]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([NH:19][N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)=[C:15]([N+:27]([O-])=O)[CH:14]=1.C(N(CC)CC)C.N1C=CC=CC=1.C1C=CC(O[C:56](OC2C=CC=CC=2)=[N:57][C:58]#[N:59])=CC=1>O1CCCC1.[Pt]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:35]=1)[O:7][CH2:8][C:9]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:10]=1/[C:11]/2=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]2[N:19]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)/[C:56](=[N:57]/[C:58]#[N:59])/[NH:27][C:15]=2[CH:14]=1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: CN1CCN(Nc2ccc(/C=C3/c4ccc(F)cc4OCc4c(F)cccc43)cc2[N+](=O)[O-])CC1
Agent: [Pt]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CN1CCN(n2/c(=N/C#N)[nH]c3cc(/C=C4/c5ccc(F)cc5OCc5c(F)cccc54)ccc32)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.1 %

Procedure:
Dissolve [4-((E)-3,7-difluoro-6H-dibenzo[b,e]oxepin-11-ylidenemethyl)-2-nitro-phenyl]-(4-methyl-piperazin-1-yl)-amine (0.008 mol, 3.96 g) in tetrahydrofuran (150 mL). Add triethylamine (0.018 mol, 1.84 g) and 10% platinum on carbon (1.3 g) and hydrogenate in a Parr shaker at 50 psi (H2) at room temperature for 3 h. Filter off the catalyst through a plug of diatomaceous earth, and add pyridine (150 mL) and diphenyl N-cyanocarbonimidate (0.009 mol, 2.17 g). Stir at room temperature for 16 h and then heat to 70° C. for 8 h. Concentrate the reaction mixture under reduced pressure. Purify on a silica gel column using 60% acetone in hexanes as eluent to obtain the title compound (1.8 g, 43%) as an off-white solid. LC-MS m/z 499.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.C(O)(=O)C.CC(OC([NH:30][CH:31]1[CH2:34][NH:33][CH2:32]1)=O)(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:49][S:50](Cl)(=[O:52])=[O:51]>ClCCCl.CCN(CC)CC>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:33]3[CH2:34][CH:31]([NH:30][S:50]([CH3:49])(=[O:52])=[O:51])[CH2:32]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CS(=O)(=O)NC1CN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-chloro-4-morpholinothieno[3,2-c]pyrimidine-6-carbaldehyde 10 from Example 3 (100 mg, 0.35 mmol) in 1,2-dichloroethane (2 mL) was added acetic acid (20 μL, 0.35 mmol), and 3-N-BOC-aminoazetidine (78 mg, 0.5 mmol) then Na(OAc)3BH (90 mg, 0.42 mmol). The reaction stirred overnight at room temperature then was quenched with water and extracted with DCM. The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was dissolved in CH2Cl2 (10 mL), MeOH (10 mL), and 4 M HCl in dioxane (10 mL) was added. The resulting mixture stirred at room temperature for 1 h then was concentrated in vacuo. The crude material was dissolved in CH2Cl2 (5 mL) and Et3N (4 mL) and methanesulfonyl chloride (110 μL, 1.4 mmol) was added. The reaction mixture stirred at room temperature overnight then was quenched by the addition of water and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo to give N-(1-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)azetidin-3-yl)methanesulfonamide which was utilized in a Suzuki coupling according to General Procedure A using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 to provide 381 after reverse phase HPLC purification (2 mg). MS (Q1) 500 (M)+
Reaction SMILES: CN([CH2:4][C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1)C.[OH-].[Na+].[C:22]([CH2:25][C:26](=[O:28])[CH3:27])(=[O:24])[CH3:23].C(C1C=C(C(C(=O)C)C(=O)C)C=C(C(C)(C)C)C=1O)(C)(C)C>>[C:16]([C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]=1[OH:15])[CH2:4][CH:25]([C:26](=[O:28])[CH3:27])[C:22](=[O:24])[CH3:23])([CH3:19])([CH3:18])[CH3:17]
Reactant: CN(C)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC(=O)CC(C)=O
Agent: CC(=O)C(C(C)=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)C(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(C)=O

Procedure:
A mixture of N,N-dimethyl-2,6-di-t-butyl-4-aminomethylphenol (2.63 g, 10 mmols), sodium hydroxide (0.6 g, 15 mmols) and acetylacetone (24 mmols, 10% solution) was refluxed for 3 hours in a glass reaction vessel. Acetylacetone was distilled under reduced pressure to afford an oily residue containing 3-(3',5'-di-t-butyl-4'-hydroxyphenyl)-2,4-pentanedione (80% by VPC). Crystallization from ethanol:water afforded a single crop of 3-(3',5'-di-t-butyl-4'-hydroxybenzyl)-2,4-pentanedione (65%, overall yield, 97% pure).
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[C:13]3[CH:26]=[CH:25][N:24]=[CH:23][C:14]3=[N:15][C:16]=2[NH:17][C@H:18]2[CH2:22][CH2:21][O:20][CH2:19]2)[CH2:7][CH2:6]1.[CH3:32][C:33](C)=[O:34].CC(OC(C)=O)=O>O1CCOCC1.[Pd]>[F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[C:13]3[CH2:26][CH2:25][N:24]([C:33](=[O:34])[CH3:32])[CH2:23][C:14]3=[N:15][C:16]=2[NH:17][C@H:18]2[CH2:22][CH2:21][O:20][CH2:19]2)[CH2:7][CH2:6]1
Reactant: Fc1ccc(OC2CCN(c3nc4ccncc4nc3N[C@H]3CCOC3)CC2)c(F)c1
Reactant: CC(C)=O
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(N[C@H]3CCOC3)nc2C1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
To a solution of (S)-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-(tetrahydrofuran-3-yl)pyrido[3,4-b]pyrazin-3-amine (2.0 g, 4.68 mmol) in dioxane:acetone (50 ml; 1.5:1) was added Ac2O (4.8 mL, 50.9 mmol) and Pd/C (400 mg, 3.76 mmol); then, the reaction was stirred at 60° C. under H2 atmosphere (345 kPa) for 72 h. The mixture was filtered through a pad of Celite™ and washed with EtOAc. The reaction solution was diluted with EtOAc (50 mL) and poured into sat. aqueous NaHCO3 (50 ml), then washed with brine (2×30 mL). The organic layer was dried over Na2SO4 and concentrated to give the crude product, which was purified by flash column chromatography to yield the title compound (193.4 mg) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.88-1.89 (m, 4H), 2.05-2.09 (m, 4H), 2.60-2.90 (m, 4H), 3.30-3.40 (m, 4H), 3.55-3.57 (m, 1H), 3.68-3.74 (m, 2H), 3.85-3.95 (m, 2H), 4.38-4.51 (m, 4H), 5.91 (dd, J=6.0, 4.4 Hz, 1H), 7.01 (m, 1H), 7.25-7.31 (m, 2H); ESI-MS m/z [M+H]+ 474.3.
Reaction SMILES: [CH2:1]1[O:14][C:13]2[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][C:3]=2[O:2]1.C(N(CC)CC)C.C(Cl)(=O)OCC.Cl.[N:29]1([C:35]2[N:44]=[C:43]([NH2:45])[C:42]3[C:37](=[CH:38][C:39]([O:48][CH3:49])=[C:40]([O:46][CH3:47])[CH:41]=3)[N:36]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>O.C(OCC)(=O)C>[CH2:1]1[O:14][C:13]2[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([N:32]3[CH2:33][CH2:34][N:29]([C:35]4[N:44]=[C:43]([NH2:45])[C:42]5[C:37](=[CH:38][C:39]([O:48][CH3:49])=[C:40]([O:46][CH3:47])[CH:41]=5)[N:36]=4)[CH2:30][CH2:31]3)=[O:10])=[CH:4][C:3]=2[O:2]1
Reactant: O=C(O)C=Cc1ccc2c(c1)OCO2
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc2nc(N3CCN(C(=O)C=Cc4ccc5c(c4)OCO5)CC3)nc(N)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 346 mg. of 3,4-methylenedioxycinnamic acid and 364 mg. of triethylamine in 20 ml. of ethyl acetate were added under ice-cooling 195 mg. of ethyl chlorocarbonate and the resulting mixture was then stirred for 4 hours. Then, 543 mg. of 2-(piperazin-1-yl)-4-amino-6,7-dimethoxyquinazoline.hydrochloride were added thereto and the resulting mixture was stirred at room temperature overnight. After 50 ml. of water were added, the precipitate thus separated was recovered by filtration. The resulting crystalline substance was recrystallized from ethanol to give 320 mg. of the desired product as the hydrochloride.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:13][C:14]1[C:15]2[C@H:22]([CH3:23])[CH2:21][CH:20]([OH:24])[C:16]=2[N:17]=[CH:18][N:19]=1.CCN(CC)CC>C(Cl)Cl.C([O-])(O)=O.[Na+]>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:24][C@@H:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([Cl:13])[C:15]=3[C@H:22]([CH3:23])[CH2:21]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:24][C@H:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([Cl:13])[C:15]=3[C@H:22]([CH3:23])[CH2:21]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C[C@@H]1CC(O)c2ncnc(Cl)c21
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(Cl)c21
Product: C[C@@H]1C[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(Cl)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 36 %
Yield: 54 %

Procedure:
Solid 4-nitrobenzoyl chloride (6.73 g, 36.3 mmol) was added to a stirred solution of (5R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol (6.09 g, 33.0 mmol) and NEt3 (5.98 mL, 42.9 mmol) in DCM (165 mL) at 0° C. The reaction was warmed to room temperature and then stirred at room temperature for 3 hours. The reaction was diluted with DCM and saturated aqueous NaHCO3. The combined extracts were washed with brine, dried MgSO4, filtered, and concentrated. The crude residue was chromatographed eluting with 10-14% EtOAc/hexane several times to give (5R,7S)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate (3.96 g, 36%) and (5R,7R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate (5.92 g, 54%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:20])=[C:10]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]=2[F:13])[C:6](=[O:21])[C:5]([C:22]([OH:24])=[O:23])=[CH:4]1)[CH3:2].[C:25]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1)(=[O:27])[CH3:26]>N1C=CC=CC=1.C1C=CC=CC=1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:20])=[C:10]([N:14]3[CH2:15][CH2:16][N:17]([S:35]([C:32]4[CH:31]=[CH:30][C:29]([NH:28][C:25](=[O:27])[CH3:26])=[CH:34][CH:33]=4)(=[O:37])=[O:36])[CH2:18][CH2:19]3)[C:11]=2[F:13])[C:6](=[O:21])[C:5]([C:22]([OH:24])=[O:23])=[CH:4]1)[CH3:2]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)c(F)c21
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(S(=O)(=O)c4ccc(NC(C)=O)cc4)CC3)c(F)c21
Reaction time: 1 h
Yield: 92.4 %

Procedure:
2.80 g of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid is suspended in 100 ml of pyridine. To this suspension is slowly added 7.76 g of 4-acetamidobenzenesulfonyl chloride in 20 ml of benzene under ice-cooling while stirring. Stirring is continued for 1 hour under ice-cooling and then for further 3 hours at room temperature. The reaction mixture is concentrated under reduced pressure. To the residue is added 1N sodium hydroxide solution to dissolve. The pH of the solution is then adjusted to 4 with acetic acid. Precipitating crystals are collected by filtration, washed with water and recrystallized from dimethylformamide (DMF)-ethanol to give 4.10 g of the titled compound. Melting point: 276°-277° C.
Reaction SMILES: C(O)C.[F:4][C:5]([F:18])([F:17])[C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][C:9]=2[CH:10]=1.[BH4-].[Na+]>C(O)(=O)C>[F:18][C:5]([F:4])([F:17])[C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:9]=2[CH:10]=1
Reactant: O=Cc1ccc2oc(C(F)(F)F)cc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: OCc1ccc2oc(C(F)(F)F)cc2c1
Temperature: 25 °C
Yield: 98.4 %

Procedure:
To an ethanol solution (2.0 mL) of 2-(trifluoromethyl)benzofuran-5-carbaldehyde (220 mg, 1.03 mmol) synthesized in Reference Synthesis Example 95, sodium borohydride (115 mg, 3.05 mmol) was added and the resultant solution was stirred at 70° C. for 1 hour and 30 minutes. After completion of the reaction, the reaction solution was cooled to room temperature and acetic acid was added to the cooled solution, followed by concentrating the resultant mixture under reduced pressure. To the obtained residue, water was added and extraction with dichloromethane from the resultant mixture was performed. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (219 mg, yield 99%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[OH-].[Na+]>>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([CH3:10])[C:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13])([CH3:5])([CH3:6])[CH3:7]
Reactant: C1COCCN1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCOCC1

Procedure:
BOC-L-Alanine (3.50 mg, 20 mmol) and morpholine (1.74 g, 20 mmol) were coupled according to procedure A (washed with 1 N NaOH after acid washes) giving a colorless oil which was used without further purification. Yield 3.94 g, 76%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].ON1C2N=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>C1COCC1.C(Cl)Cl>[N:42]1([C:7]([C:6]2[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:9])[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: C1COCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2cccnc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(c1cc([N+](=O)[O-])cc(C(F)(F)F)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
Dissolve 3-nitro-5-trifluoromethyl-benzoic acid (2.9 g, 12.6 mmol) and 1-hydroxy-7-azabenzotriazole (25 mL of 0.5 M solution in DMF) in THF. Add 1,3-dicyclohexylcarbodiimide (2.6 g, 12.6 mmol) and morpholine (1 g, 11 mmol). Stir the mixture for 48-72 hours at room temperature. Dilute the resulting suspension with DCM and quench with saturated aqueous ammonium chloride. Wash the organic layer further by aqueous saturated sodium chloride and water, dry (MgSO4) and concentrate to a yellow-white residue. Purify by silica gel column chromatography, with a gradient from 100% hexane to 50% hexane in ethyl acetate, yielding the title compound as 2.5 g white solid (75% yield). LCMS (ES), m/z 305 (M+1).
Reaction SMILES: [CH2:1]([N:5]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)[C:6](=[O:9])[CH:7]=[CH2:8])[CH2:2]C=C>C(Cl)Cl.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[F:20][C:17]([F:18])([F:19])[O:16][C:13]1[CH:12]=[CH:11][C:10]([N:5]2[CH2:1][CH2:2][CH:8]=[CH:7][C:6]2=[O:9])=[CH:15][CH:14]=1
Reactant: C=CCCN(C(=O)C=C)c1ccc(OC(F)(F)F)cc1
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Product: O=C1C=CCCN1c1ccc(OC(F)(F)F)cc1
Temperature: 45 °C
Yield: 89.7 %

Procedure:
To N-But-3-enyl-N-(4-trifluoromethoxy-phenyl)-acrylamide (0.8 g, 2.6 mmol) in DCM (20 mL) was added Grubbs catalyst (0.12 g, 0.14 mmol) and the mixture was heated to 45° C. overnight. The solvent was removed by reduced pressure and the residue was purified by silica gel column chromatography (eluting with petroleum ether/ethyl acetate=10/1) to afford the title compound (0.6 g, 82%). 1H NMR (300 MHz, CDCl3): δ 7.35-7.21 (m, 4H), 6.74-6.71 (m, 1H), 6.07-6.05 (m, 1H), 3.87-3.82 (m, 2H), 2.57-2.51 (m, 2H); LC-MS: [M+1]+ 258.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH2:7][CH2:6][CH2:5]2.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH2:23][CH2:24][Cl:25]>CC(C)=O>[Cl:25][CH2:24][CH2:23][CH2:22][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH2:7][CH2:6][CH2:5]2
Reactant: ClCCCBr
Reactant: COc1cc2c(cc1O)CCCC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc2c(cc1OCCCCl)CCCC2=O
Temperature: 25 °C
Yield: 95.4 %

Procedure:
A mixture of 6-hydroxy-7-methoxy-1-tetralone (J. Org. Chem., 1985, 50, 4937) (1.5 g, 7.8 mmol), K2CO3 (1.7 g, 12.3 mmol), and acetone (30 ml) was stirred at reflux under nitrogen for 45 minutes. The reaction was cooled to ambient temperature and a solution of 1-bromo-3-chloropropane (1.9 g, 12.1 mmol) dissolved in 8 ml acetone was dripped into the mixture. After total addition, the reaction was heated to reflux and stirred under nitrogen for 21 hours. The reaction was cooled to ambient temperature and filtered. The filter cake was washed well with acetone and the filtrate was concentrated to yield 2.0 g 6-(3-chloropropoxy)-7-methoxy-1-tetralone as an amber oil.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[F:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1.C(N(CC)C(C)C)(C)C>ClCCl.O>[F:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:3]([CH3:4])[CH3:2])(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CNC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dimethylamine hydrochloride (1.27 g) was added to a solution of 4-fluoro-benzenesulphonyl chloride (3.0 g) and N,N-diisopropylethylamine (5.37 ml) in dichloromethane (30 ml), the mixture was stirred at RT for 1 h, diluted with water, extracted with dichloromethane, dried and evaporated under reduced, yield 3.0 g.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:18][CH3:19])(=[O:17])[CH:14]([CH3:16])[CH3:15].[C:20]1([CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[O:31])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[NH4+].[Cl-]>C1COCC1.C(O)(=O)C>[OH:31][CH:30]([CH2:29][CH2:28][CH2:27][CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]([CH3:16])([CH3:15])[C:13]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C(C)C
Reactant: O=CCCCCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)C(O)CCCCc1ccccc1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 99 %

Procedure:
Diisopropylamine (7.2 mL, 52 mmol) is dissolved in THF (85 mL), cooled to -78° C. and n-butyl lithium in hexanes (23 mL, 52 mmol) is added slowly. The reaction is allowed to warm to -30° C. over 15 minutes and is then recooled to -78° C. A solution of methyl isobutyrate (6 mL, 52 mmol) in THF (15 mL) is added dropwise over 20 minutes and then stirred an additional 40 minutes. Next solution of 5-phenylpentanal (7 g, 43 mmol) in THF (10 mL) is added dropwise over 10 minutes and the reaction is stirred 1 hour. Acetic acid (3 mL) is added slowly followed by a solution of NH4Cl (20 mL) and the reaction is allowed to warm to room temperature. The reaction is partitioned between ether (200 mL) and water (150 mL). The organic phase is washed with 1 N HCl (2×50 mL), NaHCO3 (50 mL) and brine (50 mL). The solution is dried over MgSO4 and concentrated in vacuo to provide methyl 3-hydroxy-2,2-dimethyl-7-phenylheptanoate (11.2, 99%): 1H NMR (300 MHz, CDCl3) δ 7.30-7.24 (m, 2H), 7.18-7.16 (m, 3H), 3.68 (s, 3H), 3.60 (dd, J=9.7, 1.9 Hz, 1H), 2.61 (t, J=7.5 Hz, 2H), 2.37 (s, 1H), 1.73-1.20 (m, 6H), 1.17 (s, 3H), 1.15 (s, 3H); MS (EI) m/e 264 (M+).