Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[CH:2][C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[Cl-].[NH4+:12].N>CO>[CH:9]1([NH2:12])[O:10][CH2:2][C@@H:3]([OH:4])[C@@H:5]([OH:6])[C@H:7]1[OH:8]
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)CO
Reactant: [NH4+]
Agent: N
Agent: [Cl-]
Solvent: CO
Product: NC1OC[C@@H](O)[C@@H](O)[C@H]1O
Reaction time: 312 h
Yield: 932.5 %

Procedure:
To 100 ml of methanol was added 20 g of D-ribose and 0.5 g of ammonium chloride. This mixture was treated with anhydrous ammonia at 0° C. until a solution was obtained. This solution was stored at 0° C. for 13 days, then the solid was collected, giving 13 g of D-ribopyranosylamine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cl:12]N1C(=O)CCC1=O>CC(O)C>[NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[Cl:12]
Reactant: Nc1cccc2cccnc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(C)O
Product: Nc1cccc2c(Cl)ccnc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 34 %

Procedure:
8-amino quinoline (4.5 g, 31.3 mmol), N-chlorosuccinimide (4.80 g, 36 mmol) was taken up in iPrOH (50 mL) at 60° C. The mixture was heated to reflux and stirred for 20 min. The solution was cooled to 25° C. and concentrated to ⅓ original volume. The mixture was partitioned between CH2Cl2 and water. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography (5:1 hexanes/EtOAc) to afford 1.90 g (34%) of a 8-amino-4-chloro-quinoline product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[C:10](=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:9]=[C:5]([C:6]([OH:8])=O)[CH:4]=1.[NH2:19][C:20]1[NH:24][N:23]=[N:22][N:21]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[C:15]2[C:10](=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:9]=[C:5]([C:6]([NH:19][C:20]2[NH:24][N:23]=[N:22][N:21]=2)=[O:8])[CH:4]=1
Reactant: Nc1nnn[nH]1
Reactant: COc1cc(C(=O)O)nc2c([N+](=O)[O-])cccc12
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Nc2nnn[nH]2)nc2c([N+](=O)[O-])cccc12

Procedure:
4-Methoxy-8-nitroquinaldic acid (3.6 g) (see Example 16) and N,N'-carbonyldiimidazole (2.5 g) in dimethylformamide (70 ml) were heated on a steam bath for 1 hour. 5-Aminotetrazole (2.5 g) was added and the mixture was heated on a steam bath for 1 hour and cooled. 4-Methoxy-8-nitro-N(1H-tetrazol-5-yl)quinaldamide, compound with imidazole, m.p. 238°, was filtered off and was triturated with 2N hydrochloric acid (50 ml). 4-Methoxy-8-nitro-N(1H-tetrazol-5-yl)quinaldamide was collected and dried, m.p. 268° (d).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C@@H:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C@H:8]2[OH:20])[C:5](=[O:21])[CH2:4][S:3]1.[Cl:22][C:23]1[CH:40]=[CH:39][C:26]([CH2:27][N:28]2[C:36]3[C:31](=[CH:32][C:33]([CH:37]=O)=[CH:34][CH:35]=3)[CH:30]=[N:29]2)=[C:25]([C:41]([F:44])([F:43])[F:42])[CH:24]=1>>[C:16]([O:15][C:13]([N:10]1[CH2:11][CH2:12][CH:7]([N:6]2[C:5](=[O:21])/[C:4](=[CH:37]/[C:33]3[CH:32]=[C:31]4[C:36](=[CH:35][CH:34]=3)[N:28]([CH2:27][C:26]3[CH:39]=[CH:40][C:23]([Cl:22])=[CH:24][C:25]=3[C:41]([F:44])([F:42])[F:43])[N:29]=[CH:30]4)/[S:3][C:2]2=[O:1])[CH:8]([OH:20])[CH2:9]1)=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N2C(=O)CSC2=O)[C@H](O)C1
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)C(O)C1

Procedure:
(5Z)-4-{5-[1-(4-chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]-2,4-dioxothiazolidin-3-yl}-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester was prepared from 1,1-dimethylethyl trans-4-(2,4-dioxo-1,3-thiazolidin-3-yl)-3-hydroxypiperidine-1-carboxylate (from Example 270) and [4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde (from Example 1) following General Procedure F1.
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:3]1[C:17]([O:19]CC)=[O:18].[CH2:22]1[O:30][C:29]2[CH:28]=[CH:27][C:26]([Mg]Br)=[CH:25][C:24]=2[O:23]1>C1COCC1>[CH2:22]1[O:30][C:29]2[CH:28]=[CH:27][C:26]([CH:2]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH:3]3[C:17]([OH:19])=[O:18])=[CH:25][C:24]=2[O:23]1
Reactant: Br[Mg]c1ccc2c(c1)OCO2
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1=O
Solvent: C1CCOC1
Product: O=C(O)C1C(c2ccccc2)c2ccccc2C1c1ccc2c(c1)OCO2
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
To a solution of ethyl 1-oxo-3-phenylindene-2-carboxylate (1.0 g, 3.6 mmol) in THF (35 ml) under an argon atmosphere at 0° C. was added a solution of freshly prepared 3,4-methylenedioxyphenyl magnesium bromide (5.4 mmol). After stirring for 30 min, the mixture was partitioned between 3M HCl and EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3 and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 10% EtOAc/ hexanes to afford the title compound (1.03 g, 72%).
Reaction SMILES: Br[C:2]1[C:3]([CH:9]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([CH3:8])[S:5][C:6]=1[Cl:7].CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[O:34][CH2:33][CH2:32][CH2:31]3)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:16]([O:15][CH:9]([C:3]1[C:2]([C:28]2[CH:37]=[CH:36][C:35]3[O:34][CH2:33][CH2:32][CH2:31][C:30]=3[CH:29]=2)=[C:6]([Cl:7])[S:5][C:4]=1[CH3:8])[C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC1(C)OB(c2ccc3c(c2)CCCO3)OC1(C)C
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)sc(Cl)c1Br
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)sc(Cl)c1-c1ccc2c(c1)CCCO2
Temperature: 85 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
Under argon atmosphere, ethyl 2-(4-bromo-5-chloro-2-methylthiophen-3-yl)-2-(tert-butoxy)acetate (44d) (500 mg, 1.35 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman (351.8 mg, 1.35 mmol), sodium carbonate (429 mg, 4.05 mmol) were dissolved in dioxane (28 mL) and water (4 mL). The solution was degassed under argon for 10 minutes and bis(triphenylphosphine)palladium (II) dichloride (142 mg, 0.20 mmol) was added. The reaction was heated and shaken at 85° C. for 8 hours. After cooling at room temperature, the mixture was filtered through celite, rinsed with methanol. The filtrate was concentrated in vacuo and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 97/3) to give the desired product (44e) (308 mg, 0.73 mmol, 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24]CC)=[O:23])[C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15]CC)=[O:14])=[CH:8][CH:7]=1.[OH-].[K+]>>[C:22]([C:18]1[CH:19]=[CH:20][CH:21]=[C:2]([Cl:1])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:10][CH:11]=1)([OH:24])=[O:23]
Reactant: CCOC(=O)Cc1ccc(OCc2c(Cl)cccc2C(=O)OCC)cc1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)Cc1ccc(OCc2c(Cl)cccc2C(=O)O)cc1

Procedure:
Reaction of ethyl 4-(2-chloro-6-ethoxycarbonylbenzyloxy)phenylacetate with potassium hydroxide as described in Example 1c provides 4-(2-carboxy-6-chlorobenzyloxy)phenylacetic acid as a colorless solid, m.p. 171°-173° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH:11]([OH:14])[CH2:12]Br.Cl.[NH:16]1[CH2:21][CH2:20][CH:19]([N:22]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:32])[CH2:18][CH2:17]1.C(N(CC)CC)C>C(O)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH:11]([OH:14])[CH2:12][N:16]1[CH2:21][CH2:20][CH:19]([N:22]2[C:23](=[O:32])[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]2=[O:31])[CH2:18][CH2:17]1
Reactant: O=C1c2ccccc2C(=O)N1C1CCNCC1
Reactant: OC(CBr)C1COc2ccccc2O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1C1CCN(CC(O)C2COc3ccccc3O2)CC1

Procedure:
Erythro, 1-(1,4-benzodioxan-2-yl)-2-bromoethanol (1.29 g, 0.005 m) and 2-(piperid-4-yl)-1H-isoindole-1,3-(2H)dione hydrochloride (1.33 g, 0.005 cm3) in ethanol (75 cm3) with triethylamine (3.03 g, 0.03 cm3) were refluxed for 18 hours. The solution was cooled and the solvent evaporated. the residue was dissolved in chloroform and then washed twice with water, dried (MgSO4) and evaporated. The residue was dissolved in isopropyl alcohol and acidified with ethanolic HCl. The crystallised material was filtered to give the title compound as the hydrochloride salt m.p. 235°-237° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:45]=[CH:44][C:43]([F:46])=[C:42]2[C:37]=1[CH2:38][CH2:39][NH:40][CH2:41]2.N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23]([N:40]4[CH2:39][CH2:38][C:37]5[C:42](=[C:43]([F:46])[CH:44]=[CH:45][C:36]=5[F:35])[CH2:41]4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc(F)c2c1CCNC2
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cn2)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(N4CCc5c(F)ccc(F)c5C4)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 4-{4-[6-Amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB4) (245 mg, 0.517 mmol), 5,8-difluoro-1,2,3,4-tetrahydroisoquinoline (175 mg, 1.03 mmol), cupric acetate (94.8 mg, 0.517 mmol), pyridine (84 μL, 1.0 mmol), 4 Å molecular sieves (139 mg, 264 mg/mmol SM), and DCM (9 mL, 100 mmol) was stirred at rt under an atmosphere of air for 3 d. The mixture was diluted with DCM (50 ml), washed with EDTA solution (2%, 3×50 ml), water (3×50 ml) and brine (50 ml), dried over MgSO4, filtered, and concentrated in vacuo to give a dark black oil that was purified by MDPS to give the title compound as a brown solid. 1H NMR (400 MHz, CDCl3): δ=1.48 (s, 9H), 1.88-1.99 (m, 2H), 2.12-2.19 (m, 2H), 2.84-2.98 (m, 2H), 3.00 (t, J=5.6 Hz, 2H), 3.31 (t, J=6.0 Hz, 2H), 4.17 (s, 2H), 4.22-4.36 (m, 3H), 6.92-6.97 (m, 1H), 7.55 (d, J=1.6 Hz, 1H), 7.63 (s, 1H), 7.67 (s, 1H), 7.72 (d, J=1.2 Hz, 1H). MS(ES+): m/z=511.16 (100) [MH+]. HPLC: tR=2.93 min (ZQ2, polar—5 min).
Reaction SMILES: Br[C:2]1[S:6][C:5]([Cl:7])=[C:4]([CH2:8][OH:9])[CH:3]=1.[CH3:10][N:11](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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>[Cl:7][C:5]1[S:6][C:2]([C:10]#[N:11])=[CH:3][C:4]=1[CH2:8][OH:9]
Reactant: CN(C)C=O
Reactant: OCc1cc(Br)sc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1cc(CO)c(Cl)s1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of 25.0 g (5-bromo-2-chlorothiophen-3-yl)methanol in 330 mL of dimethylformamide, 25.8 g of zinc cyanide (I) and 12.7 g tetrakis(triphenylphosphine)palladium(0) were added at room temperature, and stirred at 100° C. for 4 hours. Diluting with ethyl acetate, the organic layer was washed successively with saturated aqueous ammonium chloride and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:10-1:5), to afford 16.0 g of the title compound as colorless crystals.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].Cl[CH2:19][CH2:20][CH2:21][N:22]([CH:24]([CH3:26])[CH3:25])[CH3:23].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:3][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:19][CH2:20][CH2:21][N:22]([CH:24]([CH3:26])[CH3:25])[CH3:23])=[CH:13][CH:12]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)[CH3:1]
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Reactant: CC(C)N(C)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)N(C)CCCOc1ccc(C2(CN(C)C)CCOCC2)cc1
Yield: 26.9 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (500 mg, 2.13 mmol), (3-chloro-propyl)-isopropyl-methyl-amine (318 mg, 2,13 mmol), DMF (10 ml) and K2CO3 (1.18 g, 8.52 mmol) were reacted together according to general procedure B. Purification by chromatography on silica, eluant DCM:MeOH:NH3 (96:3:1) provided the title compound (200 mg, 43%) as a white solid. 1H NMR (400 MHz, CDCl3) δ7.20 (d, 2H), 6.87 (d, 2H), 4.00 (t, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 2.83 (sep, 1H), 2.55 (t, 2H), 2.40 (s, 2H), 2.22 (s, 3H), 2.14-2.05 (m, 2H), 1.96 (s, 6H), 2.00-1.82 (m, 4H), 1.00 (d, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][CH:3]=1.N([Cl:13])=O>CCOCC>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[N:7][OH:8])=[CH:4][CH:3]=1
Reactant: O=NCl
Reactant: Cc1ccc(C=NO)cc1
Solvent: CCOCC
Product: Cc1ccc(C(Cl)=NO)cc1
Yield: 29.7 %

Procedure:
By the method of Example I-B, 167.5 g of 4-methylbenzaldoxime in 1200 ml of ether was treated with 88.4 g of nitrosyl chloride. After removal of the ether, the product was recrystallized from hexane to give 62.5 g of 4-methylbenzohydroximoyl chloride, m.p. 70°-73°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]([O:17][CH3:18])=[O:16])=[N:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1.N1C=CN=C1.[CH3:24][C:25]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])[CH3:26].C(OCC)(=O)C>CN(C=O)C>[Si:28]([O:14][CH:11]1[CH2:10][CH2:9][CH:8]([C:7]2[N:6]=[C:5]([C:15]([O:17][CH3:18])=[O:16])[CH:4]=[CH:3][C:2]=2[F:1])[CH2:13][CH2:12]1)([C:25]([CH3:27])([CH3:26])[CH3:24])([CH3:30])[CH3:29]
Reactant: COC(=O)c1ccc(F)c(C2CCC(O)CC2)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(F)c(C2CCC(O[Si](C)(C)C(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 97 %

Procedure:
To a solution of methyl 5-fluoro-6-(4-hydroxycyclohexyl)picolinate (1.0 equiv.) in DMF (0.15 M) was added imidazole (4.0 equiv.) and TBDMSCl (2.5 equiv.). The reaction mixture was stirred at room temperature for 2 days, then added to ethyl acetate, washed with water, brine, dried over magnesium sulfate, filtered and concentrated to give methyl 6-(4-(tert-butyldimethylsilyloxy)cyclohexyl)-5-fluoropicolinate in 97% yield as a mixture of isomers (3:1). LC/MS=368.3 (M+H), Rt=1.4 and 1.42 min.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]1([CH3:39])[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:25][CH:24]([O:26][S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH2:23][CH:22]2[CH2:37][OH:38])(=[O:20])=[O:19])=[CH:14][CH:13]=1.Cl>N1C=CC=CC=1>[C:12]1([CH3:39])[CH:13]=[CH:14][C:15]([S:18]([N:21]2[CH2:25][CH:24]([O:26][S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH2:23][CH:22]2[CH2:37][O:38][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])(=[O:19])=[O:20])=[CH:16][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CC(CO)N(S(=O)(=O)c3ccc(C)cc3)C2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CC(OS(=O)(=O)c3ccc(C)cc3)CN2S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
To a cooled solution of 1.83 g (9.6 mmoles) 4-toluenesulfonyl chloride in 10 mL pyridine at +10° C. was added 3.40 g (8 mmoles) of 1-(4-toluenesulfonyl)-2-hydroxymethyl-4-(4-toluenesulfonyloxy)-pyrrolidine and the mixture was stirred 18 hours. The solution obtained was then poured into 50 mL ice-cooled 2N hydrochloric acid. The precipitate was filtered, washed with water and ether. The crystalline product was purified in boiling water and ether. The crystalline product was purified in boiling ethanol to give 3.94 g of titled compound. MP 153° C. [α]D =+46.7° (c=1.9, acetone).
Reaction SMILES: [C:1]1([C:7]2[O:8]C3C(N=2)=NC=CC=3)C=CC=[CH:3][CH:2]=1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[O:24][C:25]2[C:26]([N:32]=1)=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=2.S(=O)(=O)(O)O.C(O)(=O)C>O>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[O:24][C:25]2[C:26]([N:32]=1)=[N:27][C:28]([CH3:31])=[CH:29][C:30]=2[C:7](=[O:8])[CH2:1][CH2:2][CH3:3]
Reactant: c1ccc(-c2nc3ncccc3o2)cc1
Reactant: Cc1ccc2oc(-c3ccccc3F)nc2n1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CCCC(=O)c1cc(C)nc2nc(-c3ccccc3F)oc12

Procedure:
Using the procedure described in Example 1, but replacing -phenyloxazolo[4,5-b]pyridine by 2-(2-fluorophenyl)-5-methyloxazolo[4,5-b]pyridine and using 1.5 ml of sulfuric acid, 5 ml of acetic acid (and not 7.5 ml) and 5 ml of water (and not 7.5 ml), and on purification by chromatography on silica gel (40 to 63μ; 70-230 mesh; eluent: ethyl acetate/toluene, 2:8), the product of the title is obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23].[H-].[Na+].CO>CN(C=O)C>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[CH2:15][N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(ccn2Cc2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
To a solution of methyl 1H-indole-5-carboxylate (2 g, 11.4 mmol, 1 equiv) and 1-(bromomethyl)-2,4-difluorobenzene (1.61 mL, 12.6 mmol, 1.1 equiv) in anhydrous DMF (50 mL) under argon atmosphere was added sodium hydride (913 mg, 22.8 mmol, 2 equiv) in small portions. The mixture was stirred 2 h at room temperature. The reaction mixture was then neutralized by addition of methanol and concentrated in vacuo. The residue was dissolved in AcOEt, washed with brine and dried over MgSO4. The crude was purified by flash chromatography (Hexane/AcOEt 7/3) to afford the title compound as a colorless oil (3.14 g, 10.4 mmol, 91%). ESI-MS (m/z): 302 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH2:22]Br)[CH:7]=1)[CH3:2].[CH3:25][C@@H:26]1[C@H:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:29][C:28](=[O:37])[NH:27]1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH2:22][N:27]2[C@H:26]([CH3:25])[C@H:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:29][C:28]2=[O:37])[CH:7]=1)[CH3:2]
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Cl)cc2CBr)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Cl)cc2CN2C(=O)O[C@@H](c3ccccc3)[C@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 24, Step 7, using the following starting materials: [3-(2-bromomethyl-4-chloro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([F:19])[C:17]=1[F:18])[N:14]([NH:20][CH3:21])[CH:13]=[C:12]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:11]2=[O:27].[C:28]([O:32][C:33]([C:35](=[CH2:43])[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:34])([CH3:31])([CH3:30])[CH3:29].Cl>O1CCCC1>[F:7][C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([F:19])[C:17]=1[F:18])[N:14]([N:20]([CH3:21])[CH2:43][CH:35]([C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH:13]=[C:12]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:11]2=[O:27]
Reactant: CCOC(=O)c1cn(NC)c2c(F)c(F)c(F)cc2c1=O
Reactant: C=C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(N(C)CC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2c(F)c(F)c(F)cc2c1=O
Yield: 38.3 %

Procedure:
Solid potassium tert-butoxide (823 mg) was added to tetrahydrofuran (40 ml) solution of ethyl 6,7,8-trifluoro-1-methylamino-1,4-dihydro-4-oxoquinoline-3-carboxylate (2.0 g) and tert-butyl 2-tert-butoxycarbonylacrylate (1.67 g), with stirring and suspending under ice-cooling, and the suspension was stirred for 0.5 hour with ice-cooling and then 1.5 hours at room temperature. The reaction solution was poured into a mixed liquid of ethyl acetate ice-water (150 ml/150 ml) and was adjusted to have pH of 3.0 with 1N hydrochloric acid. The organic layer was separated out, washed with water and saline solution, and dried over magnesium sulfate. This was concentrated under reduced pressure to obtain an amorphous product. The amorphous product was subjected to column chromatography with silica gel and eluted with a mixed solvent of methylene chloride ethyl acetate (20/1 to 10/1). The fractions containing the object product were collected, and the solvent was removed by distillation under reduced pressure. The residue was tritulated with n-hexane, and the precipitates were filtered out to obtain ethyl 6,7,8-trifluoro-1 -[N-methyl-N-{2,2-bis(tert-butoxycarbonyl)ethyl}amino]-1,4 -dihydro-4-oxoquinoline-3-carboxylate (1.35 g) as an almost white powder.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH2:9]=[O:10]>C1(C)C=CC=CC=1>[C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[C:3]=1[CH:9]=[O:10])[OH:2]
Reactant: Oc1cccc(O)c1
Reactant: C=O
Solvent: Cc1ccccc1
Product: O=Cc1c(O)cccc1O

Procedure:
0,1 g of dried particles of size 3.5 μm with quaternary base groups from Example 3 was dispersed in 60 g toluene in the presence of a steric stabilizer (H - 190 - 332 from ICI). Then a mixture of 1.0 g resorcinol in 2.0 g of 37% formaldehyde solution was added under stirring. After 5 hours at 50° C. monodisperse particles of size 8.3 μm had been formed.
Reaction SMILES: Cl.[F:2][C:3]([F:24])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][NH:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[C:29]12([N:39]=[C:40]=[O:41])[CH2:38][CH:33]3[CH2:34][CH:35]([CH2:37][CH:31]([CH2:32]3)[CH2:30]1)[CH2:36]2>C(Cl)Cl>[F:24][C:3]([F:2])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][N:17]([C:40]([NH:39][C:29]23[CH2:38][CH:33]4[CH2:32][CH:31]([CH2:37][CH:35]([CH2:34]4)[CH2:36]2)[CH2:30]3)=[O:41])[CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1
Reactant: Fc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: O=C(NC12CC3CC(CC(C3)C1)C2)N1CC(OC(c2ccc(F)cc2)c2ccccc2C(F)(F)F)C1
Yield: 93 %

Procedure:
To a solution of 3-[2-(trifluoromethyl)-4′-fluorobenzhydryloxy]azetidine hydrochloride (162) (200 mg, 0.55 mmol) in anhydrous DCM (5 mL) was added MP-carbonate (3.01 mmol/g; 550 mg, 1.65 mmol) and 1-adamantyl isocyanate (101 mg, 0.55 mmol). The resultant mixture was shaken at ambient temperature for 16 h, after which time it was poured onto a DCM-wetted SCX-2 (1 g) cartridge. The sample was eluted with DCM (16 mL), then evaporated to afford the desired product as a white foam (257 mg, 92%).