Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:41])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][O:31][C:32](=[O:40])[NH:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:34]1([NH:33][C:32]([O:31][CH2:30][C:10]2[CH:11]=[C:12]([O:15][CH2:16][CH2:17][C:18]3[N:19]=[C:20]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[O:21][C:22]=3[CH3:23])[CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]([OH:41])=[O:5])=[O:40])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(COC(=O)NC2CCCCC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)O)c(COC(=O)NC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.9 %

Procedure:
A 25 mL round bottomed flask was charged with 3-{2-cyclohexylcarbamoyloxymethyl-4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}-propionic acid tert-butyl ester (0.080 g, 0.14 mmol) and CH2Cl2 (2 mL). Trifluoroacetic acid (2 mL) was added, and the solution was stirred at ambient temperature under a nitrogen atmosphere for 1.5 h. The solution was concentrated to give a white solid (0.068 g, 94%). 1H NMR (400 MHz, CDCl3) 1.08-1.18 (m 3H), 1.21-1.42 (m, 2H), 1.57 (br s, 1H), 1.66-1.70 (m, 2H), 1.90 (br s, 2H), 2.40 (s, 3H), 2.61 (t, J=7.7 Hz, 2H), 2.94 (t, J=7.8 Hz, 2H), 3.01 (t, J=6.4 Hz, 2H), 3.48 (br s, 1H), 4.22 (t, J=6.4 Hz, 2H), 4.74 (br s, 1H), 5.07 (s, 2H), 6.79-6.89 (m, 1H), 6.90 (s, 1H), 7.11 (d, J=8.3 Hz, 1H), 7.44-7.46 (m, 3H), 7.98 (dd, J=6.7, 2.8 Hz, 2H). MS (ES) m/e 507 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5](Cl)=[O:6].[NH2:11][CH:12]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)[C:13]#[N:14].N1C=CC=CC=1>C1(C)C=CC=CC=1>[S:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[CH:12]([C:13]#[N:14])[NH:11][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][N:10]=[C:2]([Cl:1])[CH:3]=1
Reactant: N#CC(N)c1cccs1
Reactant: O=C(Cl)c1ccnc(Cl)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: N#CC(NC(=O)c1ccnc(Cl)c1)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.8 %

Procedure:
3 g (0.017 mol) of 2-chloroisonicotinoyl chloride was added dropwise to a solution of 2.8 g (0.02 mol) of 2-amino-2-(2-thienyl)acetonitrile and 1.6 g (0.02 mol) of pyridine in 30 ml of toluene while the temperature was kept at 10° to 15° C. The mixture was stirred at room temperature for 1 h. A saturated aqueous common salt solution was added thereto. The organic layer was separated and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and the crude product was purified according to silica gel column chromatography to obtain 1.5 g (yield: 31.8%) of light brown crystals having a melting point of 123° to 125° C.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH:10]=[CH:11][CH3:12])[N:5]=[C:4]([N:13]2[CH2:17][CH2:16][CH2:15][CH:14]2[C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:19]=2)[N:3]=1.[NH2:29][C:30]1[CH:34]=[C:33]([CH3:35])[NH:32][N:31]=1>>[CH3:35][C:33]1[NH:32][N:31]=[C:30]([NH:29][C:2]2[CH:7]=[C:6]([CH2:8][CH2:9][CH:10]=[CH:11][CH3:12])[N:5]=[C:4]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[C:18]3[O:22][N:21]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[CH:19]=3)[N:3]=2)[CH:34]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: CC=CCCc1cc(O)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Product: CC=CCCc1cc(Nc2cc(C)[nH]n2)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1

Procedure:
Starting materials: 4-hydroxy-6-(pent-3-en-1-yl)-2-[2-{3-(pyrid-2-yl)isoxazol-5-yl}pyrrolidin-1-yl]pyrimidine (Method 35) and 3-amino-5-methyl-1H-pyrazole.
Reaction SMILES: O1CCOCC1.[CH2:7]([O:9][CH:10]1[CH2:15][CH2:14][C:13](OS(C(F)(F)F)(=O)=O)=[CH:12][CH2:11]1)[CH3:8].[CH3:24][N:25]1[CH2:33][C:32]2[C:27](=[C:28]([N+:43]([O-:45])=[O:44])[CH:29]=[CH:30][C:31]=2B2OC(C)(C)C(C)(C)O2)[C:26]1=[O:46].C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH2:7]([O:9][CH:10]1[CH2:15][CH2:14][C:13]([C:31]2[CH:30]=[CH:29][C:28]([N+:43]([O-:45])=[O:44])=[C:27]3[C:32]=2[CH2:33][N:25]([CH3:24])[C:26]3=[O:46])=[CH:12][CH2:11]1)[CH3:8]
Reactant: CN1Cc2c(B3OC(C)(C)C(C)(C)O3)ccc([N+](=O)[O-])c2C1=O
Reactant: CCOC1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC1CC=C(c2ccc([N+](=O)[O-])c3c2CN(C)C3=O)CC1
Temperature: 60 °C

Procedure:
Dioxane (20 mL) and water (5 mL) were taken in a three necked RB flask equipped with a nitrogen inlet and a thermometer. The solvents were deoxygenated for 15 min using nitrogen gas. Trifluoro-methanesulfonic acid 4-ethoxy-cyclohex-1-enyl ester (Compound 166D, 300 mg, 1.1 mmol), 2-methyl-7-nitro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-isoindol-1-one (Compound 205E, 630 mg, 1.64 mmol), tetrakis triphenyl phosphine palladium catalyst (114 mg, 0.01 mmol) and cesium carbonate (889 mg, 2.7 mmol) were added. The reaction mixture was heated to 60° C. for 3 hrs. The solvents were evaporated and the residue was purified over silica gel column using (methanol:methylene chloride: 1:99). Yield: 300 mg (86%). 1H NMR (CDCl3, 400 MHz): δ1.2 (t, 3H, J=7 Hz), 1.8-2.4 (m, 6H), 3.15 (s, 3H), 3.50-3.64 (m, 3H), 4.36 (s, 2H), 5.79 (m, 1H), 7.4 (d, 1H, J=8.1 Hz), 7.63 (d, 1H, J=8.1 Hz).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.[F:12][C:13]1[CH:18]=[C:17]([CH:19]=[CH:20][N+:21]([O-])=O)[CH:16]=[CH:15][C:14]=1[O:24][CH3:25]>C(OCC)(=O)C>[F:12][C:13]1[CH:18]=[C:17]([CH2:19][CH2:20][NH2:21])[CH:16]=[CH:15][C:14]=1[O:24][CH3:25]
Reactant: COc1ccc(C=C[N+](=O)[O-])cc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COc1ccc(CCN)cc1F
Reaction time: 1 h

Procedure:
Lithium aluminum hydride (200 mL of 1 M in diethyl ether) was placed in a 1 L round bottomed flask along with 300 mL of diethyl ether. Intermediate 81 was placed in the thimble of a soxhlet extractor atop this flask and the mixture refluxed for 24 hours. The mixture was cooled to ° 0 C and 50 mL of ethyl acetate added dropwise. After stirring for 1 hour, the mixture was quenched with 100 mL of 1 N KHSO4. The Organic layer was separated washed with sat. NaHCO3, sat. NaCl, and dried over MgSO4. Removal of the solvent gave product. LC-MS showed the product had the expected M+H+ of 170. It was used in the next step without purification.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:6]=[C:5]([CH3:16])[CH:4]=1.[C:17]([N:20]1[CH2:24][C:23](=O)[N:22]=[CH:21]1)(=[O:19])[CH3:18]>>[C:17]([N:20]1[CH2:24][CH2:23][N:22]=[C:21]1[NH:2][C:3]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[N:6]=[C:5]([CH3:16])[CH:4]=1)(=[O:19])[CH3:18]
Reactant: COc1ccc(-n2nc(C)cc2N)cc1
Reactant: CC(=O)N1C=NC(=O)C1
Agent: Cl
Product: COc1ccc(-n2nc(C)cc2NC2=NCCN2C(C)=O)cc1

Procedure:
5-Amino-3-methyl-1-(4-methoxyphenyl) pyrazole HCl (Farmaco 17, 443, 1962) (23.9 g.) and 1-acetyl-2-imidazolinone (15.4 g.) were reacted as described in Example I to give 14.6 g. of product, mp 129°-131°.
Reaction SMILES: Cl[C:2]1[N:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5].[F:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>C(O)CO>[F:14][C:15]1[CH:16]=[C:17]([NH:18][C:2]2[N:13]=[CH:12][CH:11]=[CH:10][C:3]=2[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5])[CH:19]=[CH:20][CH:21]=1
Reactant: Nc1cccc(F)c1
Reactant: C#CCNC(=O)c1cccnc1Cl
Solvent: OCCO
Product: C#CCNC(=O)c1cccnc1Nc1cccc(F)c1
Temperature: 140 °C

Procedure:
Compound 8 (194 mg, 1 mmol) and 3-fluoroaniline (9f, 111 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(3-fluorophenylamino)-N-(prop-2-ynyl)nicotinamide 10f as pure product. To a solution of 2-(3-fluorophenylamino)-N-(prop-2-ynyl)nicotinamide (10f, 150 mg, 0.55 mmol) and 1-(azidomethyl)-3-phenoxybenzene (12a, 86 mg, 0.61 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 12 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 1e (220 mg, 80%); mp: 130-132° C.; 1H NMR (300 MHz, CDCl3) δ 10.62 (s, 1H), 8.31 (dd, J=3.0, 1.7 Hz, 1H), 7.83 (dd, J=3.0, 1.7 Hz, 1H), 7.78-7.73 (m, 1H), 7.59-7.53 (m, 2H), 7.36-7.18 (m, 3H), 7.12 (t, J=7.5 Hz, 1H), 6.99-6.91 (m, 5H), 6.71-6.66 (m, 2H), 5.48 (s, 2H), 4.66 ppm (d, J=5.6 Hz, 2H); MS (ESI m/z): 495 [M+H]+. Yield: 80%
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:34]=[CH:33][C:24]2[N:25]([CH2:31][CH3:32])[C:26](=[O:30])[CH2:27][CH2:28][CH2:29][C:23]=2[C:22]=1[O:35][CH3:36].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C>[Cl:19][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[N:7][C:2]([NH:20][C:21]2[CH:34]=[CH:33][C:24]3[N:25]([CH2:31][CH3:32])[C:26](=[O:30])[CH2:27][CH2:28][CH2:29][C:23]=3[C:22]=2[O:35][CH3:36])=[N:3][CH:4]=1
Reactant: CS(=O)(=O)N[C@@H]1CCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CCCc2c1ccc(N)c2OC
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CCN1C(=O)CCCc2c1ccc(Nc1ncc(Cl)c(N[C@@H]3CCC[C@H]3NS(C)(=O)=O)n1)c2OC
Temperature: 120 °C
Yield: 40.3 %

Procedure:
N-[trans-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclopentyl]-methanesulfonamide (60 mg, 0.185 mmol), 7-amino-1-ethyl-6-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (43 mg, 0.185 mmol) and camphorsulfonic acid (64 mg, 0.278 mmol) were combined in 3 mL isopropanol and heated at 120° C. in microwave for a total of 110 min. The reaction was concentrated to be taken up in dichloromethane and washed with saturated sodium bicarbonate solution (2×30 mL). The organic layer was dried over MgSO4 and filtered. The filtrate was chromatographed on a 4 g amine capped ISCO flash column from 0-100% ethyl acetate in hexanes. The product was collected as a foam after concentrating to afford 39 mg (40%) of a white foam. Compound 4: mp 141° C.; MS (ES+ calculated—523; found—524 M+H). 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J=8, 1H), 8.01 (s, 1H), 7.37 (s, 1H), 7.01 (d, J=8, 1H), 6.11 (s, 1H), 5.46 (d, 1H), 4.25 (m, 1H), 3.82 (s, 3H), 2.89 (m, 1H), 2.89 (s, 4H), 2.32 (br s, 6H), 1.89 (m, 2H), 1.73 (m, 1H), 1.59 (s, 3H), 1.15 (t, J=7, 4H) ppm.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([CH3:14])[CH:10]=[C:9]2[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.CS(O[CH2:28][C:29]1[C:34]([Cl:35])=[CH:33][CH:32]=[C:31]([N:36]([CH3:51])[C:37](=[O:50])[CH2:38][N:39]2[C:43](=[O:44])[C:42]3=[CH:45][CH:46]=[CH:47][CH:48]=[C:41]3[C:40]2=[O:49])[C:30]=1[Cl:52])(=O)=O.O>CN(C)C=O>[Cl:52][C:30]1[C:31]([N:36]([CH3:51])[C:37](=[O:50])[CH2:38][N:39]2[C:40](=[O:49])[C:41]3=[CH:48][CH:47]=[CH:46][CH:45]=[C:42]3[C:43]2=[O:44])=[CH:32][CH:33]=[C:34]([Cl:35])[C:29]=1[CH2:28][O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([CH3:14])[CH:10]=[C:9]2[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: Cc1cc(OCc2ccccn2)c2cccc(O)c2n1
Reactant: CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)c(COS(C)(=O)=O)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccccn2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN4C(=O)c5ccccc5C4=O)c3Cl)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
To a suspension of sodium hydride (59.5 mg) in N,N-dimethylformamide (0.5 ml) was added a solution of 8-hydroxy-2-methyl-4-(2-pyridylmethoxy)quinoline (600 mg) in N,N-dimethylformamide (5 ml) in ice water bath under nitrogen atmosphere, and the mixture was stirred for 30 minutes at the same condition. To the mixture was dropwise added a solution of 2,6-dichloro-3-[N-methyl-N-(phthalimidoacetyl)amino]benzyl methanesulfonate (1 g) in N,N-dimethylformamide (25 ml) in ice water bath under nitrogen atmosphere, and the mixture was stirred for 2 hours at the same temperature and for 1 day at ambient temperature. The reaction mixture was poured into water and extracted with chloroform. The organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform--methanol) to give 8-[2,6-dichloro-3-[N-methyl-N-(phthalimidoacetyl)amino]benzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoline (772 mg) as amorphous powder.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH:16][NH2:17])=[O:15])=[CH:11][CH:12]=2)[CH:7]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[CH2:6][CH:5]1[CH3:31])(=[O:3])[CH3:2].C(N(CC)CC)C.O.[O:40]1CCC[CH2:41]1>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[O:15][C:41](=[O:40])[NH:17][N:16]=3)=[CH:11][CH:12]=2)[CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)=[CH:23][CH:24]=2)[CH2:6][CH:5]1[CH3:31])(=[O:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(=O)N1c2ccc(C(=O)NN)cc2C(Nc2ccc(N3CCOCC3)cc2)CC1C
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)N1c2ccc(-c3n[nH]c(=O)o3)cc2C(Nc2ccc(N3CCOCC3)cc2)CC1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
72 mg of 1-acetyl-4-[(4-morpholinophenyl)amino]-2-methyl-1,2,3,4-tetrahydroquinoline-6-carbohydrazide (compound 133) was dissolved in 4 mL of tetrahydrofuran, and 55 mg of N,N′-carbonyldiimidazole and 47 μL of triethylamine were added to the solution. The mixture was stirred overnight at room temperature. After completion of the reaction, water was added to the mixture, and the mixture was extracted three times with chloroform. The extraction product was washed with saturated brine, dehydrated over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by using silica gel chromatography (ethyl acetate:hexane=5:1), and thus 57 mg (cis:trans=4:1, 75%) of the title compound was obtained as a pale green powder.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.Br[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=1.C([O-])(=O)C.[Cs+]>CS(C)=O.O.[Cu]>[C:11]([O:10][C:9](=[O:15])[NH:8][C@H:5]1[CH2:6][CH2:7][C@@H:2]([NH:1][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=2)[CH2:3][CH2:4]1)([CH3:12])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: Cc1ccc(Br)nc1
Agent: [Cu]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(N[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)nc1
Temperature: 100 °C
Reaction time: 17 h

Procedure:
To a round bottomed flask was added cis tert-butyl 4-aminocyclohexylcarbamate (0.5020 g, 2.342 mmol, Matrix Scientific), 2-bromo-5-methylpyridine (0.484 g, 2.81 mmol, Acros Organics), copper (0.012 g, 0.187 mmol, Fisher Scientific), and cesium acetate (2.79 g, 14.52 mmol, Sigma-Aldrich Chemical Company, Inc.) in DMSO (2.93 ml) to stir at 100° C. for 17 h. The reaction mixture was diluted with water and extracted with CH2Cl2. The organic extract was washed with ammonium hydroxide, water, saturated NaCl, dried over MgSO4, filtered and concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (50 g), eluting with a gradient of 10% to 100% EtOAc in hexane, to provide the title compound (279.5 mg, 0.915 mmol, 39.1% yield). LCMS showed product peak at 1.56 min (m+1=306.0).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[CH3:14][O:15][C:16](=[O:22])[C@@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:14][O:15][C:16](=[O:22])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[S:9]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
3,5-Dichlorobenzenesulphonyl chloride (5.0 g, 20.36 mmol) was added portionwise over 30 min to a solution of L-proline methyl ester hydrochloride (3.69 g, 22.4 mmol) and DIEA (7.8 ml, 44.8 mmol) in DCM (100 ml) at 0°. The reaction mixture was stirred overnight at room temperature then concentrated in vacuo. The residue was dissolved in EtOAc (100 ml) and washed with saturated aqueous NaHCO3 (100 ml), citric acid (10%, 100 ml) and saturated aqueous NaHCO3 (100 ml). The organic phase was dried (MgSO4) and concentrated in vacuo. Column chromatography (SiO2, EtOAc/hexane, 80:20) gave the title compound (3.77 g). δH (CDCl3) 7.8 (2H, d, J 2.0 Hz, ArH), 7.5 (1H, d, J 2.0 Hz, ArH), 4.4 (1H, m, CHα), 3.7 (3H, s, CO2Me), 3.4 (2H, m, CH2N), 2.0 (4H, m, NCH2CH2CH2); m/z (ES+, 70V), 338 (MH+).
Reaction SMILES: [Br-].[O:2]1[CH2:6][CH2:5][O:4][CH:3]1[CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:33][C:34]1[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:35]=1[CH:36]=O.O>C1COCC1>[F:33][C:34]1[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][CH2:7][CH:3]1[O:4][CH2:5][CH2:6][O:2]1
Reactant: O=Cc1cccc(F)c1F
Reactant: c1ccc([P+](CC2OCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1cccc(CCC2OCCO2)c1F
Temperature: -10 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
Well-dried (1,3-dioxolan-2-yl)methyltriphenyl phosphonium bromide (s27) (108.8 g) was mixed with THF (500 ml) under an atmosphere of nitrogen, and cooled to −10° C. Potassium t-butoxide (t-BuOK; 28.4 g) was added in two portions in the temperature range of −10° C. to −5° C. After 60 minutes of stirring at −10° C., 2,3-difluorobenzaldehyde (s26) (30.0 g) dissolved in THF (30 ml) was added dropwise in the temperature range of −10 to −5° C. After 30 minutes of stirring at 0° C., the reaction mixture was treated with water, and the aqueous layer was extracted with toluene. The combined organic layers were washed with water, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder. The purified product was dissolved in a mixed solvent of toluene (250 ml) and Solmix A-11 (250 ml), to which Pd/C (1.5 g) was added. The mixture was stirred at room temperature under a hydrogen atmosphere until hydrogen absorption had ceased. After the reaction had been completed, Pd/C was removed, and then solvent was distilled off. The residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder, and then by recrystallization from heptane to give 2-(2,3-difluorophenethyl)-1,3-dioxolane (s28) (37.9 g). The yield based on the compound (s26) was 83.8%.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:16])[CH2:7]P(OCC)(OCC)=O)[CH3:4].[F:17][C:18]([F:23])([F:22])[CH2:19][CH:20]=O>C1COCC1>[F:17][C:18]([F:23])([F:22])[CH2:19]/[CH:20]=[CH:7]/[C:6]([O:5][CH2:3][CH3:4])=[O:16]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=CCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/CC(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 37 %

Procedure:
To a stirred suspension of NaH (60% in oil, 2.15 g, 53.5 mmol) in dry THF (50 mL) was added dropwise ethyl(diethoxyphosphoryl)acetate (11 g, 49 mmol) at 0° C. under N2 atmosphere. The resulting mixture was stirred at 0° C. for 10 min and then cooled to −70° C. A solution of 3,3,3-trifluoropropanal (5.0 g, 44.5 mmol) in dry THF (50 mL) was added to the mixture at −70° C. After the addition, the stirred mixture was allowed to warm to −20° C. over 2 hrs. The reaction mixture was quenched by addition of 5% aqueous NH4Cl (100 mL) at 0° C. and extracted with EtOAc (100 mL). The organic layer was washed with brine (300 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether: EtOAc=100:1) to give the title compound (3.0 g, 37%) as a colorless oil.
Reaction SMILES: C(O[CH2:4][CH2:5][NH:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([F:19])=[C:14]([F:18])[C:15]=2[F:17])[C:10](=[O:20])[C:9]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:8]1)C.[Cl:26]C([SiH3])(Cl)Cl.C(OC(C)C)(C)C>C(#N)C>[Cl:26][CH2:4][CH2:5][NH:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([F:19])=[C:14]([F:18])[C:15]=2[F:17])[C:10](=[O:20])[C:9]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:8]1
Reactant: CCOCCNn1cc(C(=O)OCC)c(=O)c2cc(F)c(F)c(F)c21
Reactant: [SiH3]C(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CC(C)OC(C)C
Product: CCOC(=O)c1cn(NCCCl)c2c(F)c(F)c(F)cc2c1=O
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 1-(ethoxymethyl)methylamino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (200 mg) in dry acetonitrile (2.0 ml) was added trichloromethylsilane (65.8 μl) under ice -cooling and the mixture was stirred for 30 minutes, and then for 10 minutes at room temperature. To the reaction mixture was added diisopropyl ether (10 ml), which was then stirred for 15 minutes at ambient temperature. The precipitate was collected by filtration and washed with diisopropyl ether and dried in vacuo over phosphorus pentaoxide to give ethyl 1-(chloromethyl)methylamino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (145 mg).
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[O:3][C:2]1=[O:12].[H-].[Na+].I[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(OCC)(=O)C>CN(C)C=O>[CH2:16]([N:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[O:3][C:2]1=[O:12])[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCn1c(=O)oc(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
3,1-Benzoxazin-2,4-(1H)-dione (1.0 g, 6.13 mmol) was dissolved in N,N-dimethylformamide (10 ml), 60% sodium hydride (0.296 g, 7.39 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hr. 1-Iodopentane (0.97 ml, 7.32 mmol) was added, and the mixture was stirred at room temperature for 2 hr. Ethyl acetate was added to the reaction mixture, the mixture was washed with water, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give 1-pentyl-3,1-benzoxazin-2,4-(1H)-dione (0.634 g, 2.72 mmol, yield 44%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([O:22][CH3:23])[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Sn](Cl)Cl>CO>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([O:22][CH3:23])[CH:14]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C2CCN(Cc3ccccc3)C2)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CO
Product: COc1cc(C2CCN(Cc3ccccc3)C2)ccc1N
Yield: 69.6 %

Procedure:
1-Benzyl-3-(3-methoxy-4-nitro-phenyl)-pyrrolidine (350 mg, 1.12 mmol) was dissolved in methanol (20 ml), tin dichloride (1.912 g, 10.08 mmol) was added, and the reaction mixture stirred at reflux for 2 h. The methanol was evaporated, 1 N sodium hydroxide (50 ml) and ethyl acetate were added and stirring continued. The tin salts were filtered off, the organic phase was separated, dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to yield an oil (220 mg, 70%).