Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[N:6]([C:18]1[C:19]([C:25]([O:27]C)=[O:26])=[CH:20][C:21]([Cl:24])=[N:22][CH:23]=1)[C:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13](OC)=[CH:12]C=1)=O)(C)(C)C.[OH-].[Na+].C(O)(=O)C[C:33](CC(O)=O)(C(O)=O)[OH:34]>CO>[Cl:24][C:21]1[CH:20]=[C:19]([C:25]([OH:27])=[O:26])[C:18]([NH:6][CH2:7][C:9]2[CH:10]=[CH:15][C:14]([O:34][CH3:33])=[CH:13][CH:12]=2)=[CH:23][N:22]=1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: COC(=O)c1cc(Cl)ncc1N(OC(C)(C)C)C(=O)Cc1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CNc2cnc(Cl)cc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a solution of methyl 5-{(tert-butoxy)-N-[(4-methoxyphenyl)-methyl]carbonylamino}-2-chloropyridine-4-carboxilate (1 equivalent) in MeOH, was added an aqueous solution of NaOH (3 equivalents). A precipitate formed immediately. The reaction was heated until the solution was clear and was then stirred for 1 hour at room temperature. Aqueous citric acid (1 M) was then added causing the product to crash out of solution. The product was then collected to afford the title compound in 77% yield.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[N:11]1[C:15]([OH:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[N:12]1.[Br:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1>CN(C=O)C>[Br:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][O:16][C:15]2[N:11]([C:5]3[C:6]([Cl:10])=[CH:7][CH:8]=[CH:9][C:4]=3[Cl:3])[N:12]=[C:13]([C:17]([F:19])([F:20])[F:18])[CH:14]=2)=[CH:24][CH:23]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: Oc1cc(C(F)(F)F)nn1-c1c(Cl)cccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(OCc2ccc(Br)cc2)n(-c2c(Cl)cccc2Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
At 0° C. NaH (60%, 400 mg, 10 mmol) was added to a stirred mixture of 1-(2,6-dichlorophenyl)-3-trifluoromethyl-1H-pyrazol-5-ol (1.5 g, 5 mmol) and 4-bromobenzyl bromide (1.5 g, 6 mmol) in dry DMF (20 mL), the resulting mixture was stirred at ambient temperature for 1 h, then quenched with aqueous NH4Cl at 0° C., extracted with EtOAc. The combined extracts were washed with H2O and brine, dried over Na2SO4, and evaporated in vacuo. The crude product was purified by column chromatography (30% EtOAc/hexanes) to give 5-(4-bromobenzyloxy)-1-(2,6-dichlorophenyl)-3-trifluoromethyl-1H-pyrazole as a white solid (2.2 g, 94%). 1H-NMR (CDCl3): δ 7.47-7.41 (m, 4H), 7.36-7.33 (m, 1H), 7.17 (d, 2H), 5.93 (s, 1H), 5.08 (s, 2H), MS (ESI): 467[M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][N:12]=1.N#N.C(=O)([O-])[O-].[Cs+].[Cs+]>O.O1CCOCC1>[F:10][C:11]1[N:12]=[CH:13][C:14]([C:2]2[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:15][CH:16]=1
Reactant: N#Cc1cccnc1Cl
Reactant: OB(O)c1ccc(F)nc1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cccnc1-c1ccc(F)nc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To an oven-dried, N2-purged, 250-mL, round-bottomed flask containing a magnetic stir bar were added the commercially available 2-chloro-3-cyanopyridine (1.25 g, 9.00 mmol), the commercially available 2-fluoropyridine-5-boronic acid (845 mg, 6.00 mmol), and dichlorobis(triphenylphosphine)pallalium(II) (211 mg, 0.300 mmol). The flask was sealed with a septum and purged with N2 atmosphere. Anhydrous dioxane (45 mL) and a N2-purged solution of cesium carbonate (5.86 g, 18.0 mmol) in water (45 mL) were added via syringe. The reaction mixture was heated to ˜90° C. in an oil bath and stirred for 2 hours. The reaction was monitored by LC-MS. After cooling to room temperature, the solvent/volatiles were removed by rotary evaporator to give a thick brown oil. Water (75 mL) was added and the mixture was transferred to a separatory funnel. The mixture was extracted with ethyl acetate (4×30 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated by rotary evaporator to give a brown solid. The product was recrystallized from ethyl acetate/hexanes to give 1.01 g (84%) of the title compound as a tan powder. MS (ESI+) m/z 200.0 (M+H)+; 1H NMR (DMSO-d6) δ 7.43 (dd, J=8.6, 2.9 Hz, 1H), 7.70 (dd, J=8.1, 5.1 Hz, 1H), 8.49 (d, J=1.7 Hz, 1H), 8.51 (d, J=1.7 Hz, 1H), 8.74 (d, J=2.7 Hz, 1H), 8.98 (dd, J=4.7, 1.7 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][CH:23]=2)[CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]1=[O:20].C(N1C=CN=C1)(N1C=CN=C1)=O.[OH:43][CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([N:47]3[CH2:48][CH2:49][CH:44]([OH:43])[CH2:45][CH2:46]3)=[O:29])=[CH:24][CH:23]=2)[CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]1=[O:20]
Reactant: OC1CCNCC1
Reactant: O=C(O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(N4CCCCC4)C3=O)c(Cl)c2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(N4CCCCC4)C3=O)c(Cl)c2)cc1)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
Treat a solution of (R)-3′,5′-dichloro-4′-(2-oxo-1-piperidin-1-yl-pyrrolidin-3-ylmethyl)-biphenyl-4-carboxylic acid (0.102 g, 0.228 mmol) in CH2Cl2 (10 mL) with 1,1′-carbonyldiimidazole (0.074 g, 0.457 mmol) and stir for 1 hour at room temperature. Treat the reaction with 4-hydroxypiperidine (0.065 g, 0.34 mmol) and diisopropylethylamine (0.044 g, 0.34 mmol) and stir for 12 hours at room temperature. Purify the mixture on silica gel column with 100% ethyl acetate and 10% methanol in dichloromethane to afford 0.107 g (89%) of the title compound. MS (m/z): 530 (M+).
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH:16]=O)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[C:18]1([NH:24][NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO>[C:18]1([NH:24][N:25]=[CH:16][C:12]2[CH:13]=[CH:14][C:15]3[N:3]([CH2:1][CH3:2])[C:4]4[C:9]([C:10]=3[CH:11]=2)=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCn1c2ccccc2c2cc(C=O)ccc21
Reactant: NNc1ccccc1
Solvent: CO
Product: CCn1c2ccccc2c2cc(C=NNc3ccccc3)ccc21

Procedure:
9-Ethylcarbazole-3-carbaldehyde (10 g, 0.045 mol, available from Aldrich Chemical, Milwaukee, Wis.) was dissolved in 300 ml of methanol under mild heating. Then, a solution of 7.25 g (0.067 mol) of N-phenylhydrazine (from Aldrich) in methanol was added. The reaction mixture was refluxed for 2 hours to form yellowish crystals. The yellowish crystals were filtered off and washed with a large amount of methanol and dried. The yield of the product, 9-ethyl-3-carbazolecarbaldehyde N-phenylhydrazone, was 13.12 g (92%). The melting point was found to be 136–137° C. The 1H-NMR spectrum (100 MHz) of the product in CDCl3 was characterized by the following chemical shifts (δ, ppm): 1.34 (t, J=7.0 Hz, 3H, CH3); 4.23 (q, J=7.0 Hz, 2H, CH2); 6.90–7.64 (m, 8H, Ar), 7.60 (s, 1H, Ar) 7.81 (dd, 1H, Ar), 8.08 (d, 2H, Ar), 8.15 (d, 1H, ═CH). The IR spectrum of the product was characterized by the following absorption frequencies (KBr, cm−1): ν(N—H) 3306, ν(C—H) 2972, ν(arene C—H) 3051, ν(C═C, C—N in Ar) 1602; 1494; 1475; 1237, ν(C—N) 1256, γ(Ar) 815; 747; 731. The mass spectrum of the product was characterized by the following mass peaks (m/z): 314 (90%, M+1); 222 (100%, H5C12–C12H7N—CH═NH).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-:8].O[CH2:10][P+:11]([CH2:16]O)([CH2:14]O)[CH2:12]O>CC(C)=O>[Cl-:8].[NH:1]([CH2:10][P+:11]([CH2:16][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH2:14][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:12][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: OC[P+](CO)(CO)CO
Agent: [Cl-]
Solvent: CC(C)=O
Product: c1ccc(NC[P+](CNc2ccccc2)(CNc2ccccc2)CNc2ccccc2)cc1
Reaction time: 2 h
Yield: 66.5 %

Procedure:
Aniline (9.30 g) was added all at once to a slurry of 4.76 g of tetrakis(hydroxymethyl)phosphonium chloride (THPC) in 50 ml of acetone. The THPC dissolved within 1 minute, with slight warming, giving a clear solution that deposited solids on standing. After 2 hr, the mixture was filtered, giving 8.15 g (66.0 percent yield) of tetrakis(anilinomethyl)phosphonium chloride, m.p. 120°-121°. The filtrate, concentrated on a rotary evaporator, left 16.45 g of a neutral, dark yellow liquid. Beilstein tests on these products were strongly positive on the solid fraction and faintly positive on the liquid fraction, showing that most of the chlorine went into the solid fraction.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][C:5]([N:10]([C:15]2[C:34]([CH:35]3[CH2:37][CH2:36]3)=[CH:33][C:18]3[C:19]([C:29]([NH:31][CH3:32])=[O:30])=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[O:21][C:17]=3[CH:16]=2)[S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][C:3]=1[F:38].CCN(C(C)C)C(C)C.[CH2:48](Cl)[O:49][CH3:50]>C1COCC1>[Br:1][C:2]1[C:7]([CH2:8][O:9][CH2:48][O:49][CH3:50])=[CH:6][C:5]([N:10]([C:15]2[C:34]([CH:35]3[CH2:37][CH2:36]3)=[CH:33][C:18]3[C:19]([C:29]([NH:31][CH3:32])=[O:30])=[C:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[O:21][C:17]=3[CH:16]=2)[S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][C:3]=1[F:38]
Reactant: COCCl
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(F)c(Br)c(CO)c3)S(C)(=O)=O)c(C3CC3)cc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(F)c(Br)c(COCOC)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 50 °C
Reaction time: 23 h
Yield: 80.7 %

Procedure:
A mixture of 6-(N-(4-bromo-3-fluoro-5-(hydroxymethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (350 mg, 0.578 mmol), DIPEA (0.303 mL, 1.734 mmol) and MOM-Cl (0.110 mL, 1.445 mmol) in THF (3.0 mL) was stirred at 50° C. in a sealed tube. After 23 hours, the solution was concentrated and purified by silica gel chromatography (0-40% EtOAc in hexanes) to give 6-(N-(4-bromo-3-fluoro-5-((methoxymethoxy)methyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (303 mg, 70% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.59 (br. s., 1H), 0.74-0.94 (m, 2H), 0.94-1.10 (m, 1H), 1.99-2.12 (m, 1H), 3.00 (d, J=4.9 Hz, 3H), 3.27 (s, 3H), 3.37 (s, 3H), 4.61 (s, 2H), 4.71 (s, 2H), 5.85 (d, J=4.6 Hz, 1H), 7.13 (dd, J=10.0, 2.7 Hz, 1H), 7.17-7.25 (m, 2H), 7.33 (d, J=1.5 Hz, 1H), 7.48 (s, 1H), 7.58 (s, 1H), 7.83-7.92 (m, 2H). LCMS (m/z, ES+)=649, 651 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][C:12]([CH3:26])([CH3:25])[C:13]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=O)=[O:10])[CH:5]=[CH:6][CH:7]=1.C1CCN2C(=NCCC2)CC1.Cl>C(Cl)Cl>[CH3:25][C:12]1([CH3:26])[O:11][C:9](=[O:10])[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[C:13]1[C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: CC(C)(OC(=O)Cc1cccc(F)c1)C(=O)c1ccc(S(C)(=O)=O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)OC(=O)C(c2cccc(F)c2)=C1c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
A solution of the product from Step 2 (120 g) in CH2Cl2 (1 L) was treated with DBU (81.6 g) and stirred for 1 h at r.t. The reaction mixture was then treated with 1M HCl (550 mL) and the organic phase was separated, washed with saturated NaHCO3 and dried over MgSO4. After concentration, the crude was swished from 20% EtOAc/hexanes (450 mL) to give the title compound as a white solid (108.4 g, m.p. 172.7° C.).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]2)=[C:17]([Cl:29])[CH:16]=1)[C:10]([O:12]C)=[O:11].C(N(CC)CC)C.Cl[C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39].[OH-].[Li+]>FC(F)(F)C(O)=O>[CH2:41]([O:40][C:38]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]2)=[C:17]([Cl:29])[CH:16]=1)[C:10]([OH:12])=[O:11])=[O:39])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(C2CC(=O)NS2(=O)=O)c(Cl)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: O=C1CC(c2ccc(C[C@H](NC(=O)OCc3ccccc3)C(=O)O)cc2Cl)S(=O)(=O)N1
Temperature: 130 °C
Reaction time: 2 h
Yield: 51.6 %

Procedure:
Methyl (2S)-2-amino-3-[3-chloro-4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]-propanoate trifluoroacetate (50.0 mg, 0.108 mmol) was dissolved in trifluoroacetic acid (3 mL) and heated in the microwave at 130° C. for 180 s. The reaction was concentrated in vacuo and then dissolved in methanol (1.0 mL). The solution was treated with triethylamine (75.6 μL, 0.542 mmol) and benzyl chloroformate (21.7 μL, 0.152 mmol). The reaction stirred at rt for 2 h. The reaction was then treated with aqueous lithium hydroxide solution (4.0 M, 0.14 mL) and allowed to stir for 2 h. The reaction was quenched with aqueous hydrochloric acid solution (1.0 N, 1.0 mL) and purified by reverse phase HPLC to afford the product as a white solid (26 mg, 51%). LCMS found for C20H20ClN2O7S (M+H)+: m/z=467.
Reaction SMILES: [H-].[Na+].[N+:3]([CH3:6])([O-:5])=[O:4].[O:7]=[C:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][C:15]=2[F:31])[CH2:10][CH2:9]1>>[N+:3]([CH2:6][C:8]1([OH:7])[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][C:15]=2[F:31])[CH2:12][CH2:13]1)([O-:5])=[O:4]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Reactant: C[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(C[N+](=O)[O-])CC3)c(F)c2)C(=O)O1
Reaction time: 0.5 h
Yield: 17 %

Procedure:
To a stirred suspension of sodium hydride (0.72 g, 17.0 mmol) in dry tetarhydrofuran (40 ml) was added nitromethane (12.4 mmol) at 0° C. temperature. It was further stirred for 30 minutes and then (S)-N-{3-[4-(4-oxo-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (7.2 mmol) was added. The reaction mixture was stirred at 65° C. for 24 hours. The reaction mixture was poured on to crushed ice. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×20 ml). The removal of solvent afforded a crude compound, which was purified by column chromatography over silica gel to afford title compound in 17% yield. M.P. 186-187° C. and MS (M+1)=384 (MH+, 100%) M.F.=C18H23FN4O6.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[C:8]([CH3:22])=[N:9][N:10]2[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:14][C:13]([CH3:21])=[N:12][C:11]=12.FC(F)(F)C(O)=O.[N+:30]([O-])([OH:32])=[O:31]>ClCCl>[N+:30]([C:5]1[S:4][C:3]([C:7]2[C:8]([CH3:22])=[N:9][N:10]3[C:15]([CH:16]([CH2:17][CH3:18])[CH2:19][CH3:20])=[CH:14][C:13]([CH3:21])=[N:12][C:11]=23)=[C:2]([CH3:1])[CH:6]=1)([O-:32])=[O:31]
Reactant: O=[N+]([O-])O
Reactant: CCC(CC)c1cc(C)nc2c(-c3sccc3C)c(C)nn12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(CC)c1cc(C)nc2c(-c3sc([N+](=O)[O-])cc3C)c(C)nn12
Temperature: 0 °C
Yield: 76.1 %

Procedure:
Dissolve 3-(3-methyl-thiophene-2-yl)-7-(1-ethyl-propyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (0.419 g, 1.33 mmol) in dichloromethane (2.5 mL), stir under an inert atmosphere, chill in an ice bath to 0° C. and add trifluoroacetic acid (5 mL). Add concentrated (70%) nitric acid (0.132 g, 1.47 mmol) to the reaction dropwise. The solution changes color from yellow to dark green. Stir 1 h under an inert atmosphere while in an ice bath and confirm the reaction is complete using TLC. Dilute the reaction with dichloromethane (80 mL) and quench with saturated sodium bicarbonate. Separate and extract the aqueous basic phase with dichloromethane (50 mL). Combine the organic phases, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue using flash chromatography, eluting with 100% hexane/0% (30% ethyl acetate/hexane) to 0% hexane/100% (30% ethyl acetate/hexane) in a step gradient of 10% increments to give a yellow solid (0.363 g, 76%). 1H NMR (400 MHz, CDCl3): δ 7.81 (s, 1H), 6.51 (s, 1H), 3.62-3.58 (m, 1H), 2.56 (s, 3H), 2.48 (s, 3H), 2.18 (s, 3H), 1.88-1.70 (m, 4H), 0.88 (t, J=7.5 Hz, 6H).
Reaction SMILES: S([O:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([O:15][CH3:16])=[CH:8][C:7]=1[CH3:17])(=O)(=O)C.[OH-].[Na+].Cl>CO.O>[CH3:17][C:7]1[CH:8]=[C:9]([O:15][CH3:16])[C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:6]=1[OH:5]
Reactant: COc1cc(C)c(OS(C)(=O)=O)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(C)c(O)cc1[N+](=O)[O-]
Yield: 100 %

Procedure:
In 110 ml of methanol was dissolved 15.5 g (59.4 mmol) of 2-methyl-4-methoxy-5-nitropheyl mesylate. Then 6.5 g of sodium hydroxide dissolved in 20 ml of water was added thereto. The obtained mixture was heated under reflux for 1 hour. After cooling, concentrated hydrochloric acid was added to thereby acidify the mixture. Then 400 ml of water was added and crystals were precipitated. The crystals were collected by filtration and washed with water. Thus 10.9 g (59.4 mmol) of 2-methyl-4-methoxy-5-nitrophenol was obtained. The yield was 100%.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:11](=[O:12])[C@H:10]2[CH2:13][CH2:14][CH2:15][C@H:9]2[NH:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.[Br:24][CH2:25][C:26](Br)=[O:27]>C(OCC)(=O)C.CCCCCC>[Br:24][CH2:25][C:26]([N:8]1[C@@H:9]2[CH2:15][CH2:14][CH2:13][C@@H:10]2[C:11](=[O:12])[N:5]([CH2:4][C:3]2[CH:20]=[CH:21][CH:22]=[CH:23][C:2]=2[F:1])[C:6]2[CH:19]=[CH:18][CH:17]=[CH:16][C:7]1=2)=[O:27]
Reactant: O=C1[C@H]2CCC[C@H]2Nc2ccccc2N1Cc1ccccc1F
Reactant: O=C(Br)CBr
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1[C@H]2CCC[C@H]2N(C(=O)CBr)c2ccccc2N1Cc1ccccc1F
Yield: 62 %

Procedure:
Using (3aR*,10aS*)-9-(2-fluorobenzyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]-diazepin-10(1H)-one and bromoacetyl bromide, the titled compound was synthesized in substantially the same manner as in Working Example 122 in a yield of 62%, m.p. 198.5°-199.6° C. (ethyl acetate-hexane).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7](I)[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:20](OCC)=[O:21].[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:31][C:20]([C:3]2[C:2](=[O:1])[C:11]3[C:6]4=[C:7]([CH:4]=[C:3]([C@H:2]([OH:1])[CH3:11])[N:5]4[CH:4]=2)[CH:8]=[C:9]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:10]=3)=[O:21])=[CH:28][CH:27]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2c(I)cc(CN3CCOCC3)cc2c1O
Product: C[C@@H](O)c1cc2cc(CN3CCOCC3)cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn1c23
Temperature: 190 °C

Procedure:
To a flask containing ethyl 4-hydroxy-8-iodo-6-(4-morpholinylmethyl)-3-quinolinecarboxylate of Preparation 25 (3.11 g) is added 4-chlorobenzylamine (8.0 mL). The mixture is degassed under reduced pressure. The mixture is placed under an argon atmosphere and is heated at 190° C. for 3 h. The reaction is cooled to room temperature. The excess benzylamine is removed by high vacuum distillation. The residue is crystallized from acetonitrile:methanol (1:1, 800 mL) to yield 3.08 g of the title compound as a white solid:.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@H:8]([CH2:12][NH2:13])[CH2:7]1.[CH3:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@H:8]([CH2:12][NH:13][C:29](=[O:30])[CH2:28][C:25]2[CH:24]=[CH:23][C:22]([S:19]([CH3:18])(=[O:20])=[O:21])=[CH:27][CH:26]=2)[CH2:7]1
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Reactant: NC[C@@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: CS(=O)(=O)c1ccc(CC(=O)NC[C@@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)cc1
Yield: 48.8 %

Procedure:
Example 40 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 10 (0.055 g) and 4-(methylsulphonyl)phenylacetic acid (0.050 g) to give the title compound (0.046 g).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])=[CH:24][C:23]=1[O:34][CH3:35].C([O-])([O-])=O.[K+].[K+].C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([C:28](=[O:33])[C:29]([F:30])([F:31])[F:32])=[CH:24][C:23]=4[O:34][CH3:35])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1cc(C(=O)C(F)(F)F)ccc1OCCCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc(C(=O)C(F)(F)F)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 55.9 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (1.5 g, 6.7 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]-2,2,2-trifluoroethanone (2.0 g, 6.7 mmol), K2CO3 (0.88 g), KI (0.1 g) and acetonitrile (50 ml) was stirred and refluxed for 16 hours. After cooling, the reaction was poured into water and the aqueous mixture extracted with ethyl acetate. The extract was washed (H2O ), dried (MgSO4), and the solvent was concentrated to an oil, which upon evacuation at high vacuum afforded 3.2 g of a waxy solid. The solid was chromatographed on a Waters preparative LC (silica columns, eluting with 3% methanol-dichloromethane). Concentration of the appropriate fractions gave 1.8 g (56%) of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]-3-methoxyphenyl]-2,2,2-trifluoro-ethanone solid, m.p.=94°-96° C.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1.CI.[C:13](=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:13][O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(O)no1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(OC)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
2.86 g of methyl 3-hydroxyisoxazole-5-carboxylate was dissolved in 10 ml of N,N-dimethylformamide, and 4.25 g of methyl iodide and 4.15 g of potassium carbonate were then added under ice-cooling. The mixture was stirred at room temperature overnight. The reaction mixture was added to 0.1 M hydrochloric acid and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 2.23 g of methyl 3-methoxyisoxazole-5-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][C:15](OC)=[O:16])[CH:5]=[CH:6][CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][CH2:15][OH:16])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1cnoc1-c1cccc(Cl)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCc1cnoc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.4 %

Procedure:
To a solution of methyl 3-[5-(3-chlorophenyl)-4-isoxazolyl]propionate (2.50 g) in tetrahydrofuran (30 ml) was gently added diisobutylaluminum hydride (1.0 M hexane solution, 25 ml) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 3-[5-(3-chlorophenyl)-4-isoxazolyl]propan-1-ol (2.38 g, yield 95%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). NMR (CDCl3) δ: 1.39 (1H, br s), 1.84–2.00 (2H, m), 2.72–2.86 (2H, m), 3.66–3.80 (2H, m), 7.38–7.49 (2H, m), 7.56–7.68 (1H, m), 7.70–7.77 (1H, m), 8.23 (1H, s).