Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([C:13]#[C:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[O:21][C:20]([CH3:26])([CH3:25])[CH:19]=[C:18]3[C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Na+].Cl>C1COCC1.CCO>[F:1][C:2]1[CH:12]=[C:11]([C:13]#[C:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[O:21][C:20]([CH3:26])([CH3:25])[CH:19]=[C:18]3[C:27]2[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=2)[CH:10]=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)cc2)=CC(C)(C)O3)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(C2=CC(C)(C)Oc3ccc(C#Cc4ccc(C(=O)O)c(F)c4)cc32)cc1
Temperature: 35 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
To a solution of ethyl 2-fluoro-4-[[4-(4-methylphenyl)-2,2-dimethyl-(2H)-chromen-6-yl]-ethynyl]-benzoate (Compound 272, 60.0 mg, 0.136 mmol) in 2.0 mL THF and 1.0 mL EtOH was added NaOH (120.0 mg, 3.0 mmol, 3.0 mL of a 1M aqueous solution). The resulting solution was heated to 35° C., cooled to room temperature and stirred overnight. The reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before the solvent was removed under reduced pressure. The residual solid was recrystallized from CH3CN to give 53.0 mg (94%) the title compound as a colorless solid. 1H NMR (300 MHz, d6 -acetone) δ: 7.93 (1H, d, J=7.8 Hz), 7.43-7.16 (8H, m), 6.91 (1H, d, J=8.3 Hz), 5.77 (1H, s), 2.38 (3H, s), 1.49 (6H, s).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]([CH3:50])[C@H:19]([C:23]([NH:25][C@H:26]([C:30]([N:32]([C@@H:34]([C@@H:46]([CH3:49])[CH2:47][CH3:48])[C@H:35]([O:44][CH3:45])[CH2:36][C:37]([O:39]C(C)(C)C)=[O:38])[CH3:33])=[O:31])[CH:27]([CH3:29])[CH3:28])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl.C1(C)C=CC=CC=1>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([N:18]([CH3:50])[C@H:19]([C:23]([NH:25][C@H:26]([C:30]([N:32]([C@@H:34]([C@@H:46]([CH3:49])[CH2:47][CH3:48])[C@H:35]([O:44][CH3:45])[CH2:36][C:37]([OH:39])=[O:38])[CH3:33])=[O:31])[CH:27]([CH3:29])[CH3:28])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reaction time: 6 h
Yield: 122 %

Procedure:
To #7 (32 g, 46 mmol, 1 eq.) in dichloromethane (160 mL, 0.29 M) was added drop-wise over 10 minutes trifluoroacetic acid (17.4 mL, 231 mmol, 5 eq.). After 6 hours, the same amount of trifluoroacetic acid was added and the reaction was continued for 18 hours. The reaction mixture was diluted with toluene (320 mL) and concentrated in vacuo to provide #8 (35.8 g, 97%) as a pinkish oil, which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ 7.90 (d, J=7.0 Hz, 2H), 7.62 (d, J=7.4 Hz, 2H), 7.41 (br dd, J=7.4, 7.0 Hz, 2H), 7.29-7.35 (m, 2H), 4.54-4.68 (br m, 1H), [4.09 (d, J=11 Hz) and 4.22 (d, J=10.9 Hz), total 1H], 3.74-3.84 (br m, 1H), 3.22 and 3.24 (2 br s, total 3H), 2.94 and 2.96 (2 br s, total 3H), 2.78 and 2.80 (2 br s, total 3H), 2.13-2.24 (m, 1H), 1.89-2.10 (br m, 2H), 1.70-1.81 (br m, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.CN(C)P(N(C)C)(N(C)C)=O.[CH:19]([N-]C(C)C)(C)[CH3:20].[Li+].ICC>O1CCCC1.C(OCC)(=O)C>[CH2:19]([CH:3]1[C:4](=[O:7])[CH2:5][CH2:6][O:1][CH2:2]1)[CH3:20]
Reactant: O=C1CCOCC1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCC1COCCC1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
To a mixture of tetrahydropyran-4 one (5 g, 0.05 mol) and hexamethylphosphoramide (9 mL) in tetrahydrofuran (100 mL) was added lithium diisopropylamide (34.7 mL, 0.062 mol) dropwise at −78° C. under N2. After the addition the mixture was stirred for 0.5 h at −78° C. Iodoethane (7.78 g, 0.199 mol) was added to the mixture dropwise. The ddresulting mixture was stirred for 12 hours at room temperature. TLC (petroleum ether:ethyl acetate=4:1) indicated the reaction was not complete, the mixture was quenched with aqueous ammonium chloride (100 mL), extracted with ethyl acetate (3×50 mL), the combined organic layers was concentrated in vacuo and the residue was purified by chromatography on silica using petroleum ether: ethyl acetate from 15:1 to 10:1 to yield compound the title compound (2.5 g, 39.1%) as a colorless liquid. 1H NMR (400 MHz, CD3OD) δ (ppm): 4.15 (m, 2H), 3.80 (m, 1H), 3.45 (m, 1H), 2.58 (m, 1H), 2.48 (m, 2H), 1.81 (m, 1H), 1.30 (m, 1H), 0.92 (m, 3H).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16]Cl)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CCC(CCCl)CC1
Reactant: C1CCNCC1
Product: O=C(c1ccccc1)N1CCC(CCN2CCCCC2)CC1

Procedure:
A mixture of 1-benzoyl-4-(2-chloroethyl)piperidine (5.86 g), piperidine (11.52 ml) and IMS (100 ml) was boiled under reflux for 10 hours. The mixture was evaporated to near dryness and then dried by azeotropic distillation with toluene. The residue was dissolved in dichloromethane, washed with 2M sodium hydroxide solution and then brine. The separated organic layer was extracted with 2M hydrochloric acid and the combined acidic layers were basified with 2M sodium hydroxide solution and then extracted with dichloromethane to give 1-benzoyl-4-(2-piperidinoethyl)piperidine as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([F:21])[CH:20]=1)[C:5]([CH:7]1[CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]1)=[O:6].C(O)(C(F)(F)F)=O>Cl.O1CCOCC1>[NH:9]1[CH2:10][CH:7]([C:5]([C:4]2[CH:18]=[C:19]([F:21])[CH:20]=[C:2]([F:1])[CH:3]=2)=[O:6])[CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)c2cc(F)cc(F)c2)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: O=C(c1cc(F)cc(F)c1)C1CNC1

Procedure:
A solution of 400 mg (1.35 mmol) of tert-butyl 3-(3,5-difluorobenzoyl)azetidine-1-carboxylate in 6 mL of HCl in dioxane (4M) and 2.5 mL of TFA was stirred for 4 h at 50° C. The reaction mixture was concentrated, and the residue was washed with hexanes/ether (1/1) to afford the title compound. Mass Spectrum: m/e=199 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:26]#[N:27])=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][N:8]1C(OCC1C=CC=CC=1)=O.O=[C:29]([CH3:36])[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[NH2:27][C:26]1[C:3]2[C:2](=[CH:25][CH:24]=[CH:23][C:4]=2[O:5][CH2:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][NH:8]2)[N:1]=[C:29]([CH3:36])[C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: N#Cc1c(N)cccc1OCC1CCCCN1C(=O)OCc1ccccc1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OCC3CCCCN3)c2c1N

Procedure:
Prepared as in Example 2a from benzyl 2-((3-amino-2-cyanophenoxy)methyl)piperidine-1-carboxylate (Example 111c) and ethyl 3-oxobutanoate as a colorless oil (13%). MS 344 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][N:21]=[CH:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN1C(=O)N(C)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:21]=[CH:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]ncc4c3)no2)cc1Cl
Reactant: CCOC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)CCn1ncc2cc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)ccc21
Temperature: 25 °C

Procedure:
5-(5-{3-Chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indazole (D4) (200 mg) was dissolved in DMPU (2.8 ml) and treated with Cs2CO3 (367 mg) followed by ethyl 3-bromopropionate (145 ul). The resultant mixture was heated to 140° C. in a microwave reactor for 1.5 hours. The reaction mixture was then cooled to RT, evaporated to dryness and dissolved in H2O. This solution was extracted with EtOAc (×3) and the combined extracts washed with brine and evaporated to give the title compound (240 mg) as a brown oil. MS (ES): C23H2335ClN4O4 requires 454; found 455 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.Cl[C:10]([O:12][CH2:13][CH3:14])=[O:11]>N1C=CC=CC=1>[CH2:13]([O:12][C:10]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1)=[O:11])[CH3:14]
Reactant: CCOC(=O)Cl
Reactant: Nc1cccc(Br)n1
Solvent: c1ccncc1
Product: CCOC(=O)Nc1cccc(Br)n1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
10.0 g (1.0578 mole) of 2-amino-6-bromopyridine was dissolved in 40 ml dry pyridine and 6.4 ml (0.067 mole) of ethyl chloroformate was added dropwise while the solution was stirred and cooled in an ice-bath to maintain the reaction temperature at 15°-18° C. After 4 hours at room temperature, the reaction mixture was poured into 150 ml of ice water and kept at 0° C. overnight. Impure 2-ethoxycarbonylamino-6-bromopyridine was obtained by filtration and subsequently recrystallized from 2:1 methanol-water solution, giving an 88% yield of white solid, m.p=70.2°-71.0° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C1C(=O)N([Br:20])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1ccc(C)c([N+](=O)[O-])c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(CBr)c([N+](=O)[O-])c1
Reaction time: 3 h

Procedure:
4-Methyl-3-nitroanisole (2.7 mL; manufactured by Sigma-Aldrich Co.) was dissolved in carbon tetrachloride (20 mL; manufactured by Wako Pure Chemical Industries, Ltd.), and NBS (4.0520 g; manufactured by Tokyo Chemical Industry Co., Ltd.) and hydrated benzoyl peroxide (348 mg; manufactured by Sigma-Aldrich Co.) were added to the solution. The mixture was purged with nitrogen, and was stirred for 3 hours at reflux. The reaction solution was filtered, and then the filtrate was washed with an aqueous solution of NaHSO3 and water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (“COLUMN-B”; n-hexane:ethyl acetate=94:6→73:27). Thus, the title compound (3.2549 g) was obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:16])[N:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[F:11])=[O:5])C.[OH-].[Na+]>CO>[C:12]([C:9]1[C:10]([F:11])=[C:6]([C:4]([OH:5])=[O:3])[N:7]([CH3:16])[N:8]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CCOC(=O)c1c(F)c(C(C)(C)C)nn1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1nc(C(C)(C)C)c(F)c1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-tert-Butyl-4-fluoro-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (61.4 mg, 0.269 mmol, prepared as described in the previous step) was dissolved in MeOH (1 mL) then 2 M NaOH (175 μL, 0.350 mmol) was added. The resulting mixture was stirred at room temperature for 18 h and the solvent was removed under reduced pressure. The resulting residue was dissolved in H2O (10 mL) and acidified to pH˜2 using 3 M HCl. The aqueous layer was extracted with DCM (3×5 mL), the combined organic extracts were dried over MgSO4 and filtered. The solvent was removed under reduced pressure to yield 5-tert-Butyl-4-fluoro-2-methyl-2H-pyrazole-3-carboxylic acid. 1H-NMR H-NMR (400 MHz, CDCl3) δ: 9.89 (br. s., 1H), 4.06 (d, J=1.0 Hz, 3H), 1.36 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[S:3][C:4]1[CH:5]=[C:6]([CH2:22][C:23]([O:25]CC)=[O:24])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1.[OH-].[Na+]>O1CCOCC1.O>[F:28][C:2]([F:1])([F:29])[S:3][C:4]1[CH:5]=[C:6]([CH2:22][C:23]([OH:25])=[O:24])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: CCOC(=O)Cc1ccc(OCc2ccc3ccccc3n2)c(SC(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)Cc1ccc(OCc2ccc3ccccc3n2)c(SC(F)(F)F)c1

Procedure:
In analogy to the procedure of Example XV, the title compound is prepared from 2.1 g (5 mmol) of the compound from Example XXV and 0.4 g (0.01 mol) of sodium hydroxide in dioxane/water.
Reaction SMILES: [CH2:1]([C:3]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1)[CH3:2].FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([C:3]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:4][CH2:5][NH:6][CH2:7][CH2:8]1)[CH3:2]
Reactant: CCOC(=O)C1(CC)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(CC)CCNCC1
Yield: 95.8 %

Procedure:
To a stirred solution of 1-tert-butyl 4-ethyl 4-ethylpiperidine-1,4-dicarboxylate (above step 2, 4.5 g, 12.96 mmol) in 50 ml DCM was cooled to 0° C. After ten minutes trifluoro acetic acid (6.0 g) was added and stirred the reaction at room temperature for about 6 hours. Upon completion of the reaction (monitored by TLC), the reaction mixture was neutralized with saturated NaHCO3 and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure to furnish the title compound (2.3 g) as a light yellow liquid. 1H NMR (300 MHz, CDCl3): 1.19-1.24 (t, 3H); 1.48-1.58 (m, 2H); 2.14-2.18 (m, 2H); 2.64-2.73 (m, 2H); 2.86 (s, 2H); 3.01-3.07 (m, 4H); 4.10-4.17 (m, 2H); 7.07-7.10 (m, 2H); 7.24-7.30 (m, 3H); ES Mass: 186 (100%), [M+1].
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:12])[CH:8]=[C:7]([CH3:20])[C:3]=1[C:4]([OH:6])=[O:5].[CH2:21]([O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:37][CH2:38][CH3:39])[C:31]=1[N:32]1[CH:36]=[CH:35][CH:34]=[CH:33]1)[CH:27]=O)[CH3:22].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH2:21]([O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:37][CH2:38][CH3:39])[C:31]=1[N:32]1[CH:36]=[CH:35][CH:34]=[CH:33]1)[CH2:27][N:17]1[CH2:16][CH2:15][CH:14]([NH:13][C:11](=[O:12])[C:9]2[CH:10]=[C:2]([CH3:1])[C:3]([C:4]([OH:6])=[O:5])=[C:7]([CH3:20])[CH:8]=2)[CH2:19][CH2:18]1)[CH3:22]
Reactant: CCOc1cc(C=O)cc(OCC)c1-n1cccc1
Reactant: Cc1cc(C(=O)NC2CCNCC2)cc(C)c1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(C)c(C(=O)O)c(C)c3)CC2)cc(OCC)c1-n1cccc1

Procedure:
In analogy to the procedure described in example 50k), 2,6-dimethyl-N-piperidin-4-yl-terephthalamic acid (example 126b) was reacted with 3,5-diethoxy-4-pyrrol-1-yl-benzaldehyde (example 40b), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as light yellow solid. MS: 520.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[F-:12].[K+]>[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(#N)C>[Br:1][C:2]1[C:3]([F:12])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: [F-]
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Agent: [Br-]
Agent: [K+]
Agent: c1ccc([P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: O=[N+]([O-])c1cnc(F)c(Br)c1
Yield: 56.8 %

Procedure:
3-Bromo-2-chloro-5-nitropyridine (119 g, 0.500 mol, prepared according to V. Koch and S. Schnatterer, Synthesis, 1990, 497-498), potassium fluoride (79.5 g, 1.37 mol), and tetraphenylphosphonium bromide (109 g, 0.260 mol) were combined in acetonitrile (1.5 L) and heated at reflux for 4 days until GLC indicated complete consumption of the 3-bromo-2-chloro-5-nitropyridine. The volume of the mixture was reduced to 750 mL in vacuo, then the residual liquid was diluted with 2 L of ether. The mixture was filtered and the filtrate concentrated. The residue was triturated with hot hexane, and the combined hexane extracts were concentrated to give 62.8 g (54%) of the title compound: 1H NMR (DMSO-d6 300 MHz) δ 9.14 (m, 2H).
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:8][CH2:7][NH:6][C@@H:5]([C:9]([OH:11])=[O:10])[CH2:4]1.[N:12]([O-])=O.[Na+].FC(F)(F)C(OC(=O)C(F)(F)F)=O>O.CCOCC>[CH3:2][C@@H:3]1[CH2:8][CH2:7][N+:6]2=[N:12][O:10][C:9]([O-:11])=[C:5]2[CH2:4]1
Reactant: O=N[O-]
Reactant: C[C@@H]1CCN[C@@H](C(=O)O)C1
Agent: Cl
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: CCOCC
Product: C[C@@H]1CC[n+]2noc([O-])c2C1
Temperature: -5 °C
Reaction time: 2 h

Procedure:
Concentrated hydrochloric acid (6.0 ml) was added to a suspension of (2R,4R)-4-methyl-2-piperidinecarboxylic acid (Biochem. Biophys. Res. Commun. 1981; 101(2); 440) (10 g, 7.03 mmol), in water (30 ml) and this solution cooled to −5° C. A solution of sodium nitrite (5.3 g, 7.7 mmol), in water (20 ml) was then added, and this solution stirred at room temperature for 2 hours. The mixture was extracted with dichloromethane, twice, and the combined organic extracts were dried (MgSO4) and evaporated under reduced pressure to give a white solid. Trifluoroacetic anhydride (11 ml, 7.70 mmol) was added to a cooled (−3° C.) solution of the intermediate product in ether (200 ml) and the reaction stirred overnight at room temperature. The mixture was evaporated under reduced pressure, and the residue purified by column chromatography using ethyl acetate as the eluant. The title compound was obtained as a brown crystalline solid, 7.1 g.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[CH2:12][C:13](=O)[CH3:14].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]2[C:3]=1[CH:12]=[C:13]([CH3:14])[NH:9]2
Reactant: CC(=O)Cc1c([N+](=O)[O-])ccc(O)c1F
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc2c(F)c(O)ccc2[nH]1
Temperature: 25 °C
Yield: 81 %

Procedure:
1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one from previous step (50 g, 0.234 mol) was added to 2 liter round bottom flask. Water (1 L) was added, and the yellow suspension was stirred at RT. Sodium dithionite (225 g, 5.5 eq) was added in one portion and the reaction mixture was stirred and kept <30° C. until HPLC analysis indicated no starting material remained (typically less than 1 hour). Upon completion, the reaction mixture was cooled to 0° C. and the tan solid product was collected by vacuum filtration. The wet product was dried at <50° C. under house vacuum to afford 4-fluoro-2-methyl-1H-indol-5-ol (31.4 g, 81% yield) which was isolated as a tan crystalline powder. The material had an HPLC purity of >99.8. 1H NMR (CDCl3, 400 MHz) δ 7.8 (s, 1H), 6.9−6.7 (m, 2H), 6.2 (s, 1H), 4.7 (s, 1H), 2.4 (s, 3H).
Reaction SMILES: Br[C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH3:20])[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]2[O:9][C:10](=[O:12])[CH3:11])[C:5]2[CH:21]=[C:22]([Cl:26])[C:23]([Cl:25])=[CH:24][C:4]=2[N:3]=1.[CH3:27][CH2:28]CCCC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[Cl:25][C:23]1[C:22]([Cl:26])=[CH:21][C:5]2[N:6]([C@@H:7]3[O:19][C@H:18]([CH3:20])[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]3[O:9][C:10](=[O:12])[CH3:11])[C:2]([C:27]#[CH:28])=[N:3][C:4]=2[CH:24]=1
Reactant: CCCCCC
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(Br)nc2cc(Cl)c(Cl)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: C#Cc1nc2cc(Cl)c(Cl)cc2n1[C@@H]1O[C@H](C)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
2-Bromo-5,6-dichloro-1-(2,3-di-O-acetyl-5-deoxy-beta-D-ribofuranosyl)-1H-benzimidazole (0.43 g, 0.92 mmol), trimethylacetylene (Aldrich, 0.43 ml, 3.0 mmol), bis(triphenylphosphine)palladium(II) chloride (Aldrich, 0.015 g, 0.02 mmol), cuprous iodide (0.01 g, 0.05 mmol) and triethylamine (distilled from CaH, 30 mL) were combined and flushed with argon for 30 min. The solution was stirred at 25° C. for 1 h then warmed to 80° C. After 3 h the reaction mixture was concentrated and taken up in dichloromethane (100 mL) and extracted with 50 mL of 2% EDTA (Aldrich) twice then with 50 mL of H2O. The organic layer was dried with magnesium sulfate (anhyd), filtered, and evaporated. The crude residue was purified on a silica gel column (2.5×16 cm, 230-400 mesh) with 1:2 ethyl acetate: hexane with 0.1 % triethylamine to give the title compound (0.12 g, 0.28 mmol, 31%); MS (ES+): m/z (rel. intensity) 433 (100, M++Na); 1H NMR (DMSO-d6) δ8.12 (s, 1H, ArH), 8.00 (s, 1H, ArH), 6.21 (d, 1H, CH, J=6.1 Hz), 5.65 (apparent triplet, 1H, CH, J=6.8 Hz), 5.20 (apparent triplet, 1H, CH, J=6.5 Hz), 4.23-4.19 (m, CH, 1H), 2.10 (s, 3H, OAc), 1.98 (s, 3H, OAc), 1.53 (d, 3H, CH3, J=6.3 Hz).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]([C:5]1[N:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:7]2[C:12]([C:13](=[O:16])[C:14]=1[CH3:15])=[CH:11][CH:10]=[C:9]([Cl:17])[CH:8]=2)=[O:4].BrN1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.ClC(Cl)C.[N-:49]=[N+:50]=[N-:51].[Na+]>>[CH3:24][N:2]([CH3:1])[C:3]([C:5]1[N:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:7]2[C:12]([C:13](=[O:16])[C:14]=1[CH2:15][N:49]=[N+:50]=[N-:51])=[CH:11][CH:10]=[C:9]([Cl:17])[CH:8]=2)=[O:4]
Reactant: Cc1c(C(=O)N(C)C)n(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: [N-]=[N+]=[N-]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CN(C)C(=O)c1c(CN=[N+]=[N-])c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.1 %

Procedure:
In a 50 mL round bottom flask, 7-chloro-3-methyl-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid dimethylamide (0.54 g, 1.58 mmol), N-bromosuccinimide (0.367 g, 2.06 mmol) and AIBN (78 mg, 0.475 mmol) were added to dichloroethane (6.0 mL). The reaction mixture was heated to reflux for 5 hr. The mixture was concentrated to dryness and the crude (containing 3-bromomethyl-7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid dimethylamide) was redissolved in DMF (6.0 mL). To the reaction mixture was added sodium azide (0.515 g, 7.92 mmol). The reaction was stirred at room temperature overnight. The mixture was partitioned between ethyl acetate and water and the organic layer was washed with aqueous sodium bicarbonate solution. The organic layer was dried, evaporated to dryness and purified by flash chromatography using 40% ethyl acetate-hexane to afford 3-azidomethyl-7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid dimethylamide (260 mg, 43% yield).