Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]([Cl:16])[C:10]=1[CH:17]([O:19][C:20]1[C:45]([F:46])=[CH:44][C:23]2[N:24]=[C:25]([NH:27][C:28](=[O:43])[CH2:29][N:30]3[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]3)[S:26][C:22]=2[CH:21]=1)[CH3:18].C(=O)([O-])O.[Na+]>ClCCl.C(#N)C>[Cl:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]([Cl:16])[C:10]=1[CH:17]([O:19][C:20]1[C:45]([F:46])=[CH:44][C:23]2[N:24]=[C:25]([NH:27][C:28](=[O:43])[CH2:29][N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[S:26][C:22]=2[CH:21]=1)[CH3:18]
Reactant: CC(Oc1cc2sc(NC(=O)CN3CCN(C(=O)OC(C)(C)C)CC3)nc2cc1F)c1c(Cl)ccc(F)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(Oc1cc2sc(NC(=O)CN3CCNCC3)nc2cc1F)c1c(Cl)ccc(F)c1Cl
Reaction time: 16 h
Yield: 55.5 %

Procedure:
add 0.73 cm3 of trifluoroacetic acid to a solution of 0.385 g of 1,1-dimethylethyl 4-[2-({6-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-fluoro-1,3-benzothiazol-2-yl}amino)-2-oxoethyl]piperazine-1-carboxylate in 45 cm3 of dichloromethane. Stir for 16 hours at a temperature close to 20° C. The reaction mixture is then evaporated to dryness under reduced pressure (2 kPa). The residue is taken up in 15 cm3 of water. The mixture obtained is adjusted to pH 8-9 with an aqueous solution of sodium hydrogen carbonate and then extracted three times with 40 cm3 of ethyl acetate. The combined organic phases are dried over magnesium sulphate, then filtered and evaporated to dryness under reduced pressure (2 kPa). The white solid obtained is solidified in 5 cm3 of acetonitrile, filtered and then dried under reduced pressure. We obtain 0.178 g N-{6-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-fluoro-1,3-benzothiazol-2-yl}-2-(piperazin-1-yl)acetamide in the form of a cream-coloured powder, which has the following characteristics:
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([N:17](C)[C:18](=O)C(F)(F)F)[CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)=[O:4].O.S(=O)(=O)(O)O.[OH-].[Na+]>CC(=O)OCC>[Br:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([S:11]([F:16])([F:12])([F:13])([F:14])[F:15])[CH:8]=[C:7]([NH:17][CH3:18])[CH:6]=1)=[O:4]
Reactant: CN(C(=O)C(F)(F)F)c1cc(C(=O)CBr)cc(S(F)(F)(F)(F)F)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CNc1cc(C(=O)CBr)cc(S(F)(F)(F)(F)F)c1
Temperature: 80 °C
Yield: 44.5 %

Procedure:
N-[3-(2-Bromoacetyl)-5-(pentafluorosulfanyl)phenyl]-2,2,2-trifluoro-N-methylacetamide (O1.075; 1.2 g) was admixed with water (15 ml), and concentrated sulfuric acid (15 ml) was added dropwise while stirring and with ice cooling. The mixture was heated to 80° C. and stirred at this temperature for 7 h. After cooling, the reaction mixture was added slowly to a mixture of 10 N sodium hydroxide solution and EA, and the aqueous phase was extracted five times with EA. The combined organic phases were dried over magnesium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. The residue was purified by means of preparative HPLC (met. A). The product fractions, each of them clean, were combined, freed of the acetonitrile under reduced pressure, neutralized with sodium hydrogencarbonate and extracted three times with EA. The combined organic phases were dried over magnesium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 420 mg of the title compound were isolated.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([B:18]3[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]3)[C:13]=2[CH3:27])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1.C1N=CN([C:33](N2C=NC=C2)=[O:34])C=1>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[C:3]2[N:4]([C:33](=[O:34])[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([B:18]4[O:22][C:21]([CH3:23])([CH3:24])[C:20]([CH3:26])([CH3:25])[O:19]4)[C:13]=3[CH3:27])[C:9](=[O:10])[CH:8]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1c(NC(=O)Cc2ncccc2Cl)cccc1B1OC(C)(C)C(C)(C)O1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1c(=O)cc2c(Cl)cccn2c1=O
Temperature: 110 °C
Reaction time: 5 h
Yield: 64.8 %

Procedure:
A mixture of 2-(3-chloropyridin-2-yl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (0.192 g, 0.497 mmol) and CDI (0.322 g, 1.986 mmol) in toluene (2 mL) was heated at 110° C. After 5 h, the cooled mixture was diluted with EtOAc and washed sequentially with water and brine. The combined aqueous layers were extracted with EtOAc, and the combined organic phases were dried and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes, to provide racemic 5-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione as a bright yellow solid (0.133 g, 65% yield). Mass spectrum m/z 413 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ 8.26 (dt, J=7.6, 0.9 Hz, 1H), 7.94 (dd, J=7.5, 1.3 Hz, 1H), 7.36 (t, J=7.6 Hz, 1H), 7.27-7.18 (m, 2H), 6.36 (t, J=7.3 Hz, 1H), 6.31 (s, 1H), 1.57 (s, 3H), 1.36 (s, 12H).
Reaction SMILES: [OH:1][C:2]1([CH2:12][NH:13][C:14]([C:16]2[C:17]3[CH:18]=[CH:19][C:20](Cl)=[N:21][C:22]=3[CH:23]=[CH:24][C:25]=2[Cl:26])=[O:15])[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([F:11])([F:10])[F:9])[CH2:3]1.CCN(C(C)C)C(C)C.[F:37][C@H:38]1[CH2:42][CH2:41][NH:40][CH2:39]1>>[OH:1][C:2]1([CH2:12][NH:13][C:14]([C:16]2[C:17]3[CH:18]=[CH:19][C:20]([N:40]4[CH2:41][CH2:42][C@H:38]([F:37])[CH2:39]4)=[N:21][C:22]=3[CH:23]=[CH:24][C:25]=2[Cl:26])=[O:15])[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([F:11])([F:10])[F:9])[CH2:3]1
Reactant: F[C@H]1CCNC1
Reactant: O=C(NCC1(O)CCCC(C(F)(F)F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1(O)CCCC(C(F)(F)F)C1)c1c(Cl)ccc2nc(N3CC[C@H](F)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (1-hydroxy-3-trifluoromethyl-cyclohexylmethyl)-amide, DIPEA and (S)-3-fluoro-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (d, 1H), 4.72 (s, 1H), 3.80-3.58 (m, 3H), 3.26 (m, 2H), 2.59 (m, 1H), 2.22 (m, 1H), 2.08 (1H), 1.85-1.72 (m, 2H), 1.50 (m, 1H), 1.33-1.20 (m, 3H). m/z: 474 [M+H]
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH2:12][N:13]1[CH:17]=[C:16]([NH:18][C:19]([C:21]2[CH:22]=[N:23][N:24]3[CH:29]=[CH:28][CH:27]=[N:26][C:25]=23)=[O:20])[C:15]([C:30]2[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=2[O:37][CH:38]([F:40])[F:39])=[N:14]1.[BH3-]C#N.[Na+]>C1COCC1>[Cl:36][C:34]1[CH:33]=[CH:32][C:31]([O:37][CH:38]([F:40])[F:39])=[C:30]([C:15]2[C:16]([NH:18][C:19]([C:21]3[CH:22]=[N:23][N:24]4[CH:29]=[CH:28][CH:27]=[N:26][C:25]=34)=[O:20])=[CH:17][N:13]([CH2:12][CH2:11][NH:10][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=3)[N:14]=2)[CH:35]=1
Reactant: NCCn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Reactant: O=Cc1ccc(O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1cn(CCNCc2ccc(O)cc2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-hydroxybenzaldehyde (55 mg, 0.45 mmol) and N-[1-(2-aminoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (100 mg, 0.22 mmol) in THF (10 mL) was stirred at room temperature for 2 h and then NaBH3CN (28 mg, 0.45 mmol) was added. The resulting solution was stirred at room temperature overnight. The reaction was then quenched by the addition of 0.1 mL of water. The resulting mixture was concentrated under vacuum. The residue was passed through a short pad of silica gel eluting with 3% MeOH in DCM. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (34.0% MeCN up to 38.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 34.0% in 2 min); Detector, UV 254/220 nm. This resulted in 31.4 mg (23%) of the formic acid salt of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[[(4-hydroxyphenyl)methyl]amino]ethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as an off-white solid. LCMS (Method 20) [M+H]+=554.2, RT=1.58 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.74 (s, 1H), 9.34 (dd, 1H, J=1.6, 7.2 Hz), 8.69-8.67 (m, 2H), 8.37 (s, 1H), 7.62 (dd, 1H, J=2.8, 8.8 Hz), 7.60 (d, 1H, J=2.4 Hz), 7.44 (d, 1H, J=8.4 Hz), 7.28 (dd, 1H, J=4.4, 7.2 Hz), 7.10 (d, 2H, J=8.4 Hz), 7.06 (t, 1H, J=73.2 Hz), 6.68 (d, 2H, J=8.4 Hz), 4.25 (t, 2H, J=6.4 Hz), 3.63 (s, 2H), 2.95 (t, 2H, J=6.0 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:19][CH2:18][CH:14]([C:15]([OH:17])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>O1CCCC1.ClCCl>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:15]([CH:14]2[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:19][CH2:18]2)=[O:17])[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C2CCN(C(=O)OCc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
To a solution of N-benzyloxycarbonyl isonipecotic acid (123.64 g) in tetrahydrofuran (300 ml) at 0° C. was added a solution of carbonyldiimidazole (68.80 g) in tetrahydrofuran (500 ml) and dichloromethane (300 ml). The resulting solution was stirred at ambient temperature for 2 hours. This solution was cooled to 0° C. and a solution of 1-(tert-butoxycarbonyl)piperazine (87.02 g) in tetrahydrofuran (200 ml) added dropwise over minutes. The suspension obtained was stirred at ambient temperature for 48 hours. Solvent was evaporated. The residue was dissolved in diethyl ether/dichloromethane (1500 ml) and washed with water, 2M aqueous citric acid solution, saturated aqueous sodium bicarbonate solution, dried (Na2SO4) and evaporated to give 1-(tert-butoxycarbonyl)-4-[1-benzyloxycarbonylpiperidin-4-ylcarbonyl]piperazine (180.00 g) as a solid.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:43](=[O:44])[N:13]3[C:14]([C:27]([O:29]C(C4C=CC=CC=4)C4C=CC=CC=4)=[S:28])=[C:15]([C:18]4[NH:22][N:21]=[C:20]([CH2:23][C:24]([OH:26])=[O:25])[N:19]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>ClCCl.C1(OC)C=CC=CC=1.C(=O)(O)[O-].[Na+]>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:43](=[O:44])[N:13]3[C:14]([C:27]([OH:29])=[S:28])=[C:15]([C:18]4[N:19]=[C:20]([CH2:23][C:24]([OH:26])=[O:25])[NH:21][N:22]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1n[nH]c(C2=C(C(=S)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)Cc4ccccc4)[C@H]3SC2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: O=C(O)Cc1nc(C2=C(C(O)=S)N3C(=O)[C@@H](NC(=O)Cc4ccccc4)[C@H]3SC2)n[nH]1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 9.5 %

Procedure:
To a solution of benzhydryl 7β-(2-phenylacetamido)-3-(3-carboxymethyl-1,2,4-triazol-5-yl)thio-3-cephem-4-carboxylate (370 mg) in a mixture of dichloromethane (1.2 ml) and anisole (0.4 ml) was added trifluoroacetic acid (0.8 ml) under ice-cooling. The mixture was stirred at room temperature for 50 minutes. The reaction mixture was poured into diisopropyl ether (30 ml), and the resulting precipitate was collected by filtration and dried in vacuo. The precipitate was dissolved in a mixture of aqueous sodium hydrogen carbonate (58 mg/30 ml), tetrahydrofuran (10 ml) and ethyl acetate (30 ml). To the separated aqueous layer was added tetrahydrofuran (10 ml) and ethyl acetate (30 ml), adjusted to pH 2.0 with 1N-hydrochloric acid. The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with isopropyl ether to give crude product (190 mg). The crude product (175 mg) was dissolved in a mixture of aqueous sodium bicarbonate (62 mg/10 ml), purified by high pressure liquid chromatography (HPLC) (R-ODS-C-15, YMC-pack) eluting with 20% acetonitrile-phosphate buffer (pH 3.0). The solution was concentrated in vacuo. To the resulting solution was added tetrahydrofuran (10 ml) and ethyl acetate (40 ml) and adjusted to pH 2.2 with 1N-hydrochloric acid. The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated in vacuo. The residue was triturated with isopropyl ether to give 7β-(2-phenylacetamido)-3-(5-carboxymethyl-1,2,4-triazol-3-yl)thio-3-cephem-4-carboxylic acid (25.7 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=[O:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[Cl:16][CH2:17][CH2:18]OS(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:18][CH2:17][Cl:16])[C:10]1[C:9](=[O:15])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCCC3=O
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)c1c(n2CCCl)C(=O)CCC1

Procedure:
100 g. (0.5 mole) of 6-methyl-1,2,3,4-tetrahydrocarbazol-1-one and 234.5 g. (1 mole) of p-toluenesulfonic acid-β-chloroethylester are dissolved in 700 ml. of toluene and stirred together with a solution of 4.25 g. (12.5 m moles) of tetrabutylammoniumhydrogensulfate in 500 ml. of aqueous sodium hydroxide solution (30% strength) for 10 hours at room temperature. The organic layer is separated, washed with water and concentrated by evaporation. 108 g. (=83% of the theoretical) of 6-methyl-9-(2-chloroethyl)-1,2,3,4-tetrahydrocarbazol-1-one (melting at 106° to 107° C.) are thus obtained.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][CH2:8][CH2:9][OH:10].C(Cl)(C(Cl)=O)=O.CS(C)=O.C(N(CC)CC)C.C(OCCC(CC=C)CO)C1C=CC=CC=1>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][CH2:8][CH:9]=[O:10]
Reactant: OCCCC(CCOCc1ccccc1)C1OCCO1
Agent: C=CCC(CO)CCOCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CCCC(CCOCc1ccccc1)C1OCCO1
Yield: 28.8 %

Procedure:
The alcohol (15 (16.8 g, 59.92 mmol), prepared according to Example 13, was oxidized using 2 M (COCl)2 (37.50 mL, 75 mmol), dry DMSO (10.6 mL, 150 mmol), and triethylamine (43 mL, 300 mmol) as for the oxidation of compound 12. Similar work up as for 13 gave a crude product, which was purified by column chromatography eluting with ether/hexane (2:1), to give the aldehyde 16 (4.8 g, 81%) as a colorless oil. IR (KBr)νmax 29.42, 2878, 2725, 1723, 1496, 1434, 1413, 1368, 1211, 1153, 1098, 1031, 951, 742, 661 cm−1; 1HNMR (CDCl3)δ 1.56-1.86 (m, 5 H), 2.52 (t, J=7.6 Hz, 2H), 3.52-3.57 (m, 2H), 3.79-3.92 (m, 4 H), 4.48 (s, 2 H), 4.75 (d, J=3.3 Hz, 1 H), 7.25-7.34 (m, 5 H), 9.71 (s, 1 H); 13CNMR (CDCl3)δ 21.48, 29.33, 38.00, 41.71, 64.79, 68.73, 72.82, 106.28, 127.42, 127.55, 128.55, 128.25, 138.48; mass spectrum (EI), m/z (rel intensity) 279 (M+−1.7.5), 219(7), 171 (15), 144(8), 127(53), 91(31), 83(9), 73(100), 65(4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24].[C:25](=O)([O-])[O-].[K+].[K+].CN(C)C=O.CI>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:25])[C:7](=[O:12])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1c(-c2ccccc2Cl)c2cc(Cl)ccc2[nH]c1=O
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccccc2Cl)c2cc(Cl)ccc2n(C)c1=O

Procedure:
To a mixture of ethyl 6-chloro-4-(2-chlorophenyl)-1,2-dihydro-2-oxo-3-quinolinecarboxylate(1.81 g), potassium carbonate powder (0.7 g), and N,N-dimethylformamide (DMF) (20 ml) was dropwise added methyl iodide (0.37 g) under stirring. The mixture was stirred for 2.5 hours, diluted with water and then extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and distilled to remove the solvent. The residue was crystallized with isopropyl ether to obtain ethyl 6-chloro-4-(2-chlorophenyl)-1,2-dihydro-1-methyl-2-oxo-3-quinolinecarboxylate. Recrystallization from ethanol gave colorless prisms. mp 139°-140° C.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5](=O)[CH3:6].[F:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][NH2:17])=[CH:12][CH:11]=1>C(O)(=O)C>[F:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:3](=[O:2])[CH2:4][C:5]([CH3:6])=[N:17]2)=[CH:12][CH:11]=1
Reactant: NNc1ccc(F)cc1
Reactant: COC(=O)CC(C)=O
Solvent: CC(=O)O
Product: CC1=NN(c2ccc(F)cc2)C(=O)C1
Temperature: 120 °C
Yield: 69 %

Procedure:
To a solution of 3-oxo-butyric acid methyl ester (2.8 g) in acetic acid (6.5 mL) in a round bottom flask under argon was added 4-fluorophenylhydrazine (3.05 g). The mixture was immersed into an oil bath and heated to 120° C. overnight. The reaction vessel was then cooled and the acetic acid was evaporated in vacuo and the remaining solid was dissolved in EtOAc and water. The phases were separated and the aqueous phase was extracted with further EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo and azeotroped with toluene (2×). The crude residue was then purified via ISCO Combiflash chromatography using EtOAc/heptane as eluent to afford the desired 2-(4-fluoro-phenyl)-5-methyl-2,4-dihydro-pyrazol-3-one (3.2 g) as a beige solid. MS (ESI+): 193.3 ([M+H]+).
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].[CH2:22]([C:24]([C:42]1[CH:47]=[CH:46][C:45](O)=[C:44]([CH3:49])[CH:43]=1)([C:27]1[CH:32]=[CH:31][C:30]([C:33]#[C:34][C:35]2([OH:40])[CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:29]([CH3:41])[CH:28]=1)[CH2:25][CH3:26])[CH3:23].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:22]([C:24]([C:42]1[CH:47]=[CH:46][C:45]([O:12][S:9]([C:8]([F:21])([F:20])[F:7])(=[O:11])=[O:10])=[C:44]([CH3:49])[CH:43]=1)([C:27]1[CH:32]=[CH:31][C:30]([C:33]#[C:34][C:35]2([OH:40])[CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:29]([CH3:41])[CH:28]=1)[CH2:25][CH3:26])[CH3:23]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(C#CC2(O)CCCC2)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(CC)(c1ccc(C#CC2(O)CCCC2)c(C)c1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Reaction time: 0.17 h
Yield: 51.1 %

Procedure:
Pyridine (0.97 mL, 12 mmol) and trifluoromethanesulfonic anhydride (1.3 mL, 7.7 mmol) were added to a solution of 4-{1-ethyl-1-[4-(1-hydroxy-cyclopentylethynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (Example 32-(1); 3 g, 8 mmol) in dichloromethane (30 mL) at −10° C., and the mixture was stirred at the same temperature for 10 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane only to hexane/ethyl acetate=4/1) to give the title compound (2 g, 49%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:9]=[C:10]([CH:22]=[CH:23][CH:24]=1)[CH2:11][O:12][CH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.O.[OH-].[Na+]>C1COCC1>[F:7][C:8]1[CH:9]=[C:10]([CH:22]=[CH:23][CH:24]=1)[CH2:11][O:12][CH2:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1
Reactant: N#Cc1ccc(COCc2cccc(F)c2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc(COCc2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.6 %

Procedure:
To a LiAlH4 (2.00 g, 53.4 mmol) suspension in THF (300 mL) was added dropwise a THF (20 mL) solution of 4-(((3-fluoro)benzyloxy)methyl)benzonitrile (4.30 g, 17.8 mmol) at 0° C. The mixture was stirred at room temperature (16 h) and H2O (1.6 mL) was added dropwise at 0° C. followed by an aqueous NaOH solution (0.8 mL, 15% w/w), and then H2O (1.6 mL). The mixture was stirred at room temperature (2 h), and the precipitate filtered and washed with CH2Cl2. The filtrate was concentrated in vacuo and the solid triturated with Et2O to obtain a white solid (1.60 g, 37%). The solid was used in the next step with no other purification: Rf=0.00 (hexanes/EtOAc 8/2); mp >138° C. (decomp.); IR (nujol) 3224, 3100, 3039, 2970, 2843, 1593, 1520, 1456, 1375, 1257, 1143, 1073, 940, 866, 733, 686, 549 cm−1; 1H NMR (CDCl3) δ 3.87 (s, CH2NH2), 4.47-4.54 (m, 2 CH2O), 7.08-7.45 (m, 8 ArH); 13C NMR (CDCl3) δ 43.1 (CH2N), 70.4, 71.2 (2 CH2O), 113.8 (d, J=21.7 Hz, C2′ or C4′), 114.1 (d, J=20.5 Hz, C4′ or C2′), 123.1 (d, J=2.3 Hz, C6′), 127.5 (ArC), 128.1 (ArC), 130.2 (d, J=8.0 Hz, C5′), 137.2, 137.3 (2 ArC), 141.4 (d, J=6.8 Hz, C1′), 162.1 (d, J=242.5 Hz, C3′); HRMS (M+H+) (ESI+) 246.1294 [M+H+] (calcd for C15H16FNOH+ 246.1294).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[N:6][C:7]=1[CH3:8].CCN(C(C)C)C(C)C.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[C:21]([C:20]([F:19])([F:30])[F:31])[CH:22]=2)[CH:5]=[N:6][C:7]=1[CH3:8]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Cc1ncc(N)cc1Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To a 0.4 M solution of 5-bromo-6-methylpyridin-3-amine (1.00 equiv.) in DCM was added DIEA (1.00 equiv.) and 3-(trifluoromethyl)benzoyl chloride (1.00 equiv.). The mixture was stirred at ambient temperature for 3 hr. The reaction mixture was diluted with DCM, washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated to give N-(5-bromo-6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamide as an off-white solid in 98% yield. LCMS (m/z) (M+H)=359.0/361.0, Rt=0.86 min.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10](OS(C)(=O)=O)[CH2:9][C@H:8]1[CH2:17][OH:18])=[O:6])[CH:2]=[CH2:3].[Cl-].[NH4+].[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C)C=O.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([N:21]=[N+:22]=[N-:23])[CH2:9][C@H:8]1[CH2:17][OH:18])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CO
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1C[C@@H](N=[N+]=[N-])C[C@H]1CO
Temperature: 75 °C

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-2-hydroxymethyl-4-methanesulfonyloxypyrrolidine (20.0 g) in N,N-dimethylformamide (200 ml) were added ammonium chloride (5.74 g) and sodium azide (6.98 g). The resulting mixture was heated at 75° C. for 8 hours. After cooling, the mixture was diluted with ethyl acetate (1 l) and aqueous sodium hydrogen carbonate (1 l). The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated in vacuo to give (2S,4S)-1-allyloxycarbonyl-4-azido-2-hydroxymethylpyrrolidine.