Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S([O-])([O-])=O.[Na+:5].[Na+].C(=O)(O)[O-].[Na+].[Cl:12][C:13]1[CH:14]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1>O>[Cl:12][C:13]1[CH:14]=[C:15]([S:19]([O-:21])=[O:20])[CH:16]=[CH:17][CH:18]=1.[Na+:5]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=S([O-])c1cccc(Cl)c1
Temperature: 65 °C
Reaction time: 0.08 h
Yield: 65.3 %

Procedure:
A solution of sodium sulphite (627 mg, 4.98 mmol) and sodium bicarbonate (418 mg, 4.98 mmol) in water (13 mL) was stirred vigorously with 3-chlorobenzenesulfonyl chloride (500 mg, 2.36 mmol) at 0° C. for 30 min then heated at 65° C. for 3 h. After cooling to ambient temperature, the reaction mixture was washed with dichloromethane (2×20 mL) and lyophilized. The resulting white solid was stirred with methanol (10 mL) for 5 min and the insoluble inorganic salts removed by filtration. The filtrate was concentrated in vacuo to approximately 3 mL and an equal volume of diethyl ether added. The precipitated solid containing residual inorganic salts was filtered and set aside. The remaining filtrate was diluted with excess diethyl ether, filtered and the filtered solid dried in vacuo to give sodium 3-chloro-benzenesulfinate (306 mg, 65%) as a white solid: 1H NMR (DMSO-d6, 300 MHz) δ 7.43 (br s, 1H), 7.35-7.39 (m, 1H), 7.32 (d, J=7.2 Hz, 1H), 7.26 (dt, J=7.5, 1.8 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22]([CH3:25])(=[O:24])=[O:23])=[N:7][C:8]2[C:13]([CH:14]=1)=[N:12][CH:11]=[C:10]([F:15])[CH:9]=2)(O)C.[C:26]1(=[O:36])[NH:30][C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O>C1COCC1>[F:15][C:10]1[CH:9]=[C:8]2[C:13]([CH:14]=[C:5]([CH:2]([N:30]3[C:26](=[O:36])[C:27]4[C:28](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:29]3=[O:31])[CH3:1])[C:6]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[S:22]([CH3:25])(=[O:23])=[O:24])=[N:7]2)=[N:12][CH:11]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(O)c1cc2ncc(F)cc2nc1-c1ccccc1S(C)(=O)=O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(c1cc2ncc(F)cc2nc1-c1ccccc1S(C)(=O)=O)N1C(=O)c2ccccc2C1=O
Reaction time: 0.17 h

Procedure:
To a mixture of methyl 1-(7-fluoro-2-(2-(methylsulfonyl)phenyl)-1,5-naphthyridin-3-yl)ethanol (500 mg, 1.44 mmol) and phthalimide (425 mg, 2.88 mmol) in THF (15 mL) was added triphenylphosphene (757 mg, 2.88 mmol) at 0° C. The reaction mixture was stirred for 10 min at same temperature. Diisopropyl azo-dicarboxylate (0.6 mL, 2.88 mmol) was added to reaction mixture at 0° C. The reaction mixture was stirred for overnight at 0° C. Water was added to reaction mixture and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo to give 2-(1-(7-fluoro-2-(2-(methylsulfonyl)phenyl)-1, 5-naphthyridin-3-yl)ethyl) isoindoline-1,3-dione: LC-MS (ESI) m/z 476.0 [M+H]+. It was carried on crude for next step.
Reaction SMILES: O([C:8]([N:10]([O:40]C(OC1C=CC=CC=1)=O)[CH:11]([CH3:39])[C:12]#[C:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[N:19]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)=[CH:28][N:27]=1)[CH2:18][CH2:17]2)=[O:9])C1C=CC=CC=1.[NH3:50]>>[NH2:50][C:8]([N:10]([CH:11]([CH3:39])[C:12]#[C:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[N:19]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)=[CH:28][N:27]=1)[CH2:18][CH2:17]2)[OH:40])=[O:9]
Reactant: CC(C#Cc1ccc2c(c1)CCN(Cc1ccc(-c3ccc(F)cc3)cn1)C2=O)N(OC(=O)Oc1ccccc1)C(=O)Oc1ccccc1
Reactant: N
Product: CC(C#Cc1ccc2c(c1)CCN(Cc1ccc(-c3ccc(F)cc3)cn1)C2=O)N(O)C(N)=O
Temperature: -78 °C

Procedure:
An NH3 (10 mL) solution of 6-{3-[N,O-bis(phenoxycarbonyl)hydroxylamino]-1-butyn-1-yl}-2-{[5-(4-fluorophenyl)-2-pyridyl]-methyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline (310 mg, 0.47 mmol) in a sealed tube is stirred at ambient temperature for 12 hours. The mixture is then cooled to -78° C. and the reaction vessel carefully opened. The ammonia is allowed to evaporate and the resulting material is partitioned between EtOAc (60 mL) and H2O (10 mL). The aqueous phase is extracted with EtOAc (1×25 mL) and the combined organic phases are washed with saturated NaHCO3 solution (2×50 mL), saturated NaCl solution (2×5 mL), dried over MgSO4 and concentrated in vacuo- The resulting pale yellow solid is chromatographed (silica gel, EtOAc then 10% MeOH/CH2Cl2) to afford 6-[3-(N-aminocarbonyl-N-hydroxyamino)-1-butyn-1-yl]-2-{[5-(4-fluorophenyl)-2-pyridyl]-methyl}-1-oxo-1,2,3,4 -tetrahydroisoquinoline, m.p. 118°-120°C.
Reaction SMILES: C(OC([NH:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][NH:19]C(OC(C)(C)C)=O)=O)(C)(C)C>CCOC(C)=O.Cl>[NH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][NH2:8]
Reactant: CC(C)(C)OC(=O)NOCCOCCOCCONC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: NOCCOCCOCCON
Yield: 27.2 %

Procedure:
Compound 36 (559 mg, 1.47 mmol) was dissolved in 15 mL of of EtOAc, and HCl gas was bubbled through the solution for 30 minutes. The mixture was concentrated under vacuum to provide 72 mg (90%) of compound 37 as the HCl salt as a sticky residue: 1H NMR (D2O) δ 3.75 (s, 4H), 3.87 (m, 4H), 4.27 (m, 4H); mass spectrum (ES) m/z calculated for C6H17N2O4 (M+H): 181.1. Found: 181.1.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[C:5]1=[O:14])[CH2:2][CH3:3].N1C2C(=CC=CC=2)C(=O)[C:16]1=O.BrCCCC>>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[C:5]1=[O:14])[CH2:2][CH2:3][CH3:16]
Reactant: CCCN1C(=O)C(=O)c2ccccc21
Reactant: O=C1Nc2ccccc2C1=O
Solvent: CCCCBr
Product: CCCCN1C(=O)C(=O)c2ccccc21

Procedure:
Was made in an analogous fashion to 1-propylindoline-2,3-dione by reacting commercially available isatin (purchased from Fisher Scientific) with 1-bromo-butane (purchased from Fisher Scientific). 1H-NMR δ 7.68 (m, 2H), 7.11 (dd, 1H), 6.90 (d, 1H), 3.72 (t, 2H), 1.65 (q, 2H), 1.41 (m, 2H), 0.97 (t, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([C:22]3[N:23](CC4C=CC=CC=4)[N:24]=[N:25][C:26]=3[C:27]([F:30])([F:29])[F:28])=[O:21])[CH2:16][CH2:15]2)=[CH:12][CH:13]=1)=[O:7]>CO.C(O)(=O)C.[Pd]>[CH3:1][CH:2]([CH3:38])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:15][CH2:16][N:17]([C:20]([C:22]3[NH:23][N:24]=[N:25][C:26]=3[C:27]([F:29])([F:28])[F:30])=[O:21])[CH2:18][CH2:19]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3c(C(F)(F)F)nnn3Cc3ccccc3)CC2)nn1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3[nH]nnc3C(F)(F)F)CC2)nn1
Reaction time: 8 h
Yield: 36.3 %

Procedure:
6-[4-(3-Benzyl-5-trifluoromethyl-3H-[1,2,3]triazole-4-carbonyl)piperazin-1-yl]pyridazine-3-carboxylic acid (3-methylbutyl)amide (0.4 g, 0.75 mmol) was dissolved in 10 mL of MeOH with 3 drops of acetic acid and 0.2 g of 10% Pd/C was added. The reaction mixture was kept under normal pressure of H2 at ambient temperature overnight. After filtration the reaction mixture was evaporated under reduced pressure and the residue was recrystallized from 3 mL of EtOH to give 120 mg (36% yield) of 6-[4-(5-trifluoromethyl-3H-[1,2,3]triazole-4-carbonyl)-piperazin-1-yl]pyridazine-3-carboxylic acid (3-methylbutyl)amide as a white powder. 1H NMR (500 MHz, Acetone-d6) δ 8.18, 7.91, 7.32, 3.92-3.72, 3.45, 1.67, 1.52, 0.92.
Reaction SMILES: Br[CH2:2][CH:3]1[O:7][CH2:6][CH2:5][O:4]1.[CH:8]([NH2:12])([CH2:10][CH3:11])[CH3:9].[OH-].[Na+]>O>[CH:8]([NH:12][CH2:2][CH:3]1[O:7][CH2:6][CH2:5][O:4]1)([CH2:10][CH3:11])[CH3:9]
Reactant: CCC(C)N
Reactant: BrCC1OCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC(C)NCC1OCCO1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
2-Bromomethyl-1,3-dioxolane (20 grams) and sec-butylamine (120 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at a temperature of about 100° C. for a period of about 3 hours. After this time sodium hydroxide (10 grams) dissolved in water (100 ml) was added and the resulting mixture was stirred for a period of about 30 minutes. The reaction mixture was then extracted with ether and the ether solution was separated and dried over magnesium sulfate. The dried solution was filtered and stripped of solvent to yield the desired product N-sec-butyl-N-(1,3-dioxolan-2-ylmethyl)amine as an oil.
Reaction SMILES: C(O)(=O)/C=C\C(O)=[O:5].[CH3:9][N:10]1[CH2:15][CH:14]=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1.[Br-].[Na+].BrBr.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>O.C(Cl)(Cl)Cl>[CH3:9][N:10]1[CH2:11][CH2:12][C:13]2([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)[CH:14]([O:5]2)[CH2:15]1
Reactant: Cc1ccc(C2=CCN(C)CC2)cc1
Reactant: O=C(O)/C=C\C(=O)O
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C23CCN(C)CC2O3)cc1
Reaction time: 0.25 h

Procedure:
1-Methyl-4-(4-methylphenyl)-1,2,3,6-tetrahydropyridine maleate (5.0 g, 16.4 mmoles, described in Example 3) is suspended in water (60 ml) and a solution of sodium bromide (5.15 g, 49.9 mmoles) and bromine (0.84 ml) in water (50 ml) is added dropwise to the cooled mixture (<5° C.). The reaction mixture is stirred for 15 min., potassium carbonate (20 g) is added followed by chloroform (100 ml) and a solution of sodium hydroxide pellets (680 mg) in water (10 ml). After stirring vigorously for 15 min., the layers are separated and the aqueous solution is extracted with chloroform. The combined extracts are washed with brine, dried (MgSO4) and evaporated. The residue is triturated with pentane to give the title compound, mp 124°-125.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][N:23]=1)[C:17]([O:19][CH3:20])=[O:18].[CH3:24][N:25]([CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1)[C:26]([C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](O)=[O:32])=[O:27].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH3:24][N:25]([CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1)[C:26]([C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][N:23]=1)[C:17]([O:19][CH3:20])=[O:18])=[O:32])=[O:27]
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)O)c1
Reactant: COC(=O)c1ccnc(-c2cc(N3CCCCC3)ccc2N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(C(=O)N(C)CCN3CCOCC3)c2)c1
Reaction time: 2 h
Yield: 81.9 %

Procedure:
A solution of 150 mg of methyl 2-(2-amino-5-(piperidin-1-yl)phenyl)isonicotinate 1.1h, 169 mg of 3-(methyl(2-morpholinoethyl)carbamoyl)benzoic acid, and 249 mg of diisopropylethylamine in 3 mL of DMF was treated with 202 mg of HATU. The mixture was stirred for 2 h and then it was diluted with 20 mL of water. The resulting precipitate was collected by filtration and dissolved in dichloromethane. The solution was washed with water and then dried over Na2SO4. The solvent was evaporated to give the product as 231 mg of an orange oil.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[C:9](=[O:15])[NH:10][CH:11]=[CH:12][C:13]=1[I:14].Br[CH2:17][CH2:18][C:19]([CH3:29])([S:25]([CH3:28])(=[O:27])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C1COCC1>[F:7][C:8]1[C:9](=[O:15])[N:10]([CH2:17][CH2:18][C@@:19]([CH3:29])([S:25]([CH3:28])(=[O:27])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:11]=[CH:12][C:13]=1[I:14]
Reactant: O=c1[nH]ccc(I)c1F
Reactant: CCOC(=O)C(C)(CCBr)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@](C)(CCn1ccc(I)c(F)c1=O)S(C)(=O)=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
Cesium carbonate (1.50 g, 4.60 mmol) was added to a solution of 3-fluoro-4-iodopyridin-2(1H)-one (354 mg, 1.48 mmol) and ethyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate (595 mg, 2.07 mmol in THF (25 mL). The resulting suspension was heated to 50° C. and stirred overnight. The reaction was heated to 70° C. and stirred at this temperature overnight. The reaction was filtered through celite (˜1 inch), and the filter pad was washed with ethyl acetate (2×30 ml). The combined filtrates were concentrated and the crude was purified via flash chromatography on an Analogix SF15-24 g column and an eluant of ethyl acetate in heptane (50-100%) to afford the title compounds as a clear gum (366 mg, 55.5%). LC-MS m/z 445.9 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.35 (t, J=7.12 Hz, 3H) 1.76 (s, 3H) 2.43-2.56 (m, 2H) 3.11 (s, 3H) 3.97-4.10 (m, 1H) 4.20-4.38 (m, 3H) 6.50 (dd, 1H) 6.75-6.98 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:39]=[CH:38][C:5]([O:6][C@@H:7]2[C@@H:15]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C@H:14]([CH3:24])[O:13][C:12](=[O:25])[C@@H:11]([NH:26][C:27](=[O:37])[C:28]3[C:33]([OH:34])=[C:32]([O:35][CH3:36])[CH:31]=[CH:30][N:29]=3)[CH2:10][O:9][CH2:8]2)=[CH:4][CH:3]=1.[C:40](Cl)(=[O:42])[CH3:41]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:40]([O:34][C:33]1[C:28]([C:27](=[O:37])[NH:26][C@H:11]2[CH2:10][O:9][CH2:8][C@H:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:39][CH:38]=3)[C@@H:15]([O:16][C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C@H:14]([CH3:24])[O:13][C:12]2=[O:25])=[N:29][CH:30]=[CH:31][C:32]=1[O:35][CH3:36])(=[O:42])[CH3:41]
Reactant: COc1ccnc(C(=O)N[C@H]2COC[C@H](Oc3ccc(F)cc3)[C@@H](Oc3ccc(F)cc3)[C@H](C)OC2=O)c1O
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccnc(C(=O)N[C@H]2COC[C@H](Oc3ccc(F)cc3)[C@@H](Oc3ccc(F)cc3)[C@H](C)OC2=O)c1OC(C)=O
Temperature: 40 °C
Reaction time: 14 h
Yield: 80.1 %

Procedure:
To a solution of N-((3S,7S,8S,9S)-7,8-bis(4-fluorophenoxy)-9-methyl-2-oxo-1,5-dioxonan-3-yl)-3-hydroxy-4-methoxypicolinamide (54 mg, 0.099 mmol) in DCM (0.5 mL) was added TEA (0.028 mL, 0.198 mmol), DMAP (6.1 mg, 0.050 mmol), and acetyl chloride (0.011 ml, 0.149 mmol). The reaction was warmed to 40° C. for and stirred for 14 h. The reaction was then concentrated and the crude residue purified by flash chromatography (SiO2, EtOAc/Hexanes) to give the title compound as a white foam (46.5 mg, 80%): IR (thin film) 3372, 2939, 1765, 1676 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.78 (d, J=8.2 Hz, 1H), 8.37 (d, J=5.4 Hz, 1H), 7.03 (d, J=5.5 Hz, 1H), 6.98-6.86 (m, 6H), 6.74-6.61 (m, 2H), 5.33-5.24 (m, 1H), 5.14 (m, 1H), 4.36 (t, J=9.2 Hz, 1H), 4.30-4.22 (m, 1H), 4.10-3.99 (m, 2H), 3.92 (s, 3H), 3.92-3.87 (m, 1H), 3.79 (dd, J=11.2, 7.3 Hz, 1H), 2.40 (s, 3H), 1.48 (d, J=6.4 Hz, 3H); HRMS-FAB (m/z) [M+H]+ calcd for C29H28F2N2O9, 587.1836; found, 587.1838.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[O:15][CH2:16][CH3:17])=[O:4].[C:18]([O-:21])(=[O:20])[CH3:19].[Na+]>CN(C)C=O>[CH2:16]([O:15][C:6]1[CH:7]=[CH:8][C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]=1[C:3](=[O:4])[CH2:2][O:21][C:18](=[O:20])[CH3:19])[CH3:17]
Reactant: CCOc1ccc2ccccc2c1C(=O)CBr
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc2ccccc2c1C(=O)COC(C)=O
Temperature: 80 °C
Yield: 93.8 %

Procedure:
A mixture of 2-bromo-1-(2-ethoxy-naphthalen-1-yl)-ethanone (7.0 g), sodium acetate (2.0 g) and N,N-dimethylformamide (80 mL) was heated at 80° C. for 1.5 hours. After cooling to room temperature the N,N-dimethylformamide was removed under reduced pressure and the resulting residue was partitioned between dichloromethane (60 mL) and water (60 mL). The organic phase was washed with water (60 mL), brine (60 mL), dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to afford acetic acid 2-(2-ethoxy-naphthalen-1-yl)-2-oxo-ethyl ester (6.1 g, 94%) as dark red oil. 1H NMR (CDCl3): 1.45 (3H, t, J=7.0 Hz), 2.2 (3H, s), 4.2 (2H, q, J=7.0 Hz), 5.15 (2H, s), 7.2 (1H, d, J=9.4 Hz), 7.35 (1H, m), 7.45 (1H, m), 7.75 (1H, d, J=8.1 Hz), 7.85 (2H, m).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:6]2[C:16]([CH3:20])=[C:17]([CH3:19])[S:18][C:5]=2[N:4]2[C:21]([CH3:24])=[N:22][N:23]=[C:3]12.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35]>C(Cl)(Cl)Cl>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([C:7]2[C:6]3[C:16]([CH3:20])=[C:17]([CH3:19])[S:18][C:5]=3[N:4]3[C:21]([CH3:24])=[N:22][N:23]=[C:3]3[CH:2]([NH:1][C:34]([NH:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[O:26][CH3:25])=[O:35])[N:8]=2)=[CH:14][CH:13]=1
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC(N)c1nnc(C)n1-2
Reactant: COc1ccccc1N=C=O
Solvent: ClC(Cl)Cl
Product: COc1ccccc1NC(=O)NC1N=C(c2ccc(Cl)cc2)c2c(sc(C)c2C)-n2c(C)nnc21
Reaction time: 0.5 h

Procedure:
6-Amino-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- f][1,2,4]triazolo[4,3-a][1,4]diazepine (4 g) was dissolved in chloroform (30 ml). 2-Methoxyphenyl isocyanate (1.7 ml) was added, and the mixture was stirred for 30 minutes. The reaction mixture was subjected to silica gel column chromatography, and the resultant crystals were recrystallized from ethanol to give 5.14 g of N-(4-(4-chlorophenyl)-2,3,9- trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin- 6-yl)-N'-(2-methoxyphenyl)urea, melting point 261°-262° C.
Reaction SMILES: [CH2:1]1[O:19][C:18]2[C:3](=[CH:4][C:5]([N+:20]([O-:22])=[O:21])=[C:6]([CH:17]=2)[C:7]([N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]([OH:16])=[O:15])=[O:8])[O:2]1.CO.[CH2:25](O)[CH3:26]>>[CH2:1]1[O:19][C:18]2[C:3](=[CH:4][C:5]([N+:20]([O-:22])=[O:21])=[C:6]([CH:17]=2)[C:7]([N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]([O:16][CH2:25][CH3:26])=[O:15])=[O:8])[O:2]1
Reactant: CCO
Reactant: O=C(O)C1CCCN1C(=O)c1cc2c(cc1[N+](=O)[O-])OCO2
Solvent: CO
Product: CCOC(=O)C1CCCN1C(=O)c1cc2c(cc1[N+](=O)[O-])OCO2
Yield: 85 %

Procedure:
By carrying out the procedure as in Example 11, but replacing 4-hydroxy-1-(3,4-methylenedioxybenzoyl)pyrrolidine-2-carboxylic acid by 1-(4,5-methylenedioxy-2-nitrobenzoyl)pyrrolidine-2-carboxylic acid and methanol by ethanol, the title product is obtained.
Reaction SMILES: O[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:12][C:13]([CH:15]1[CH2:19][CH2:18][CH2:17][N:16]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])=[O:14].O>P(Cl)(Cl)(Cl)=O>[CH2:23]([O:22][C:20]([N:16]1[CH2:17][CH2:18][CH2:19][CH:15]1[C:13]1[O:14][C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=2[N:12]=1)=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1cccc(NC(=O)C2CCCN2C(=O)OCc2ccccc2)c1O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1cccc2nc(C3CCCN3C(=O)OCc3ccccc3)oc12
Temperature: 25 °C
Yield: 44.7 %

Procedure:
A mixture of benzyl 2-(2-hydroxy-3-(methoxycarbonyl)phenylcarbamoyl)pyrrolidine-1-carboxylate (400 mg, 1 mmol) in phosphoryl trichloride (5 mL) was heated to reflux for 40 mins. The mixture was cooled to room temperature and poured into water (100 mL) carefully with vigorous stirring, then extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=30:1 to 8:1) to give methyl 2-(1-(benzyloxycarbonyl)pyrrolidin-2-yl)benzo[d]oxazole-7-carboxylate (170 mg, yield 45%). LC-MS (ESI) m/z: 381 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH2:25][CH2:26][CH3:27])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:24])=[N:15][N:16]2[C:21]([OH:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=12)=[O:12])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:31][C:32]1[C:37]([F:38])=[C:36]([O:39][CH3:40])[CH:35]=[CH:34][C:33]=1[F:41].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.ClCCl>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH2:25][CH2:26][CH3:27])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:24])=[N:15][N:16]2[C:21]([O:22][CH2:31][C:32]3[C:33]([F:41])=[CH:34][CH:35]=[C:36]([O:39][CH3:40])[C:37]=3[F:38])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=12)=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(F)c(CCl)c1F
Reactant: CCCC(C)(CNC(=O)c1c(C)nn2c(O)cc(C)cc12)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3c(F)ccc(OC)c3F)cc(C)cc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 80 mg (0.20 mmol) of rac-(1-{[(7-hydroxy-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl)carbonyl]amino}-2-methylpentan-2-yl)carbamic acid tert-butyl ester from Example 141A and 38 mg (0.20 mmol) of 2-(chloromethyl)-1,3-difluoro-4-methoxybenzene from Example 133A in 2 ml of DMF was admixed with 129 mg (0.396 mmol) of caesium carbonate. The resulting suspension was stirred at RT for 72 h. The reaction mixture was diluted with dichloromethane (15 ml) and extracted with saturated aqueous sodium hydrogencarbonate solution (10 ml). The organic phase was concentrated under reduced pressure, which gave a crude material that contained the target compound in a multicomponent mixture (30% pure). The crude material was used in the next step without further purification.
Reaction SMILES: [SH:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.Cl[CH2:13][CH2:14][OH:15]>[OH-].[Na+]>[OH:15][CH2:14][CH2:13][S:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(S)ccc1O
Reactant: OCCCl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(SCCO)ccc1O
Yield: 84 %

Procedure:
85 g (0.5 mole) of 5-mercaptosalicylic acid were reacted at room temperature with 41.5 g (0.5 mole) β-chloroethanol in 500 ml sodium hydroxide solution of 20% strength, whereby 90 g 5-(β-hydroxyethyl-mercapto)-salicylic acid melting at 136° C. were obtained (yield 71% of theory). 120 g (0.55 mole) of the aryl-alkyl sulfide obtained were oxidized in 200 ml glacial acetic acid at 65° C. with 215 ml 30% hydrogen peroxide whereby 103 g 5-(β-hydroxyethyl-sulfonyl)-salicyclic acid (yield 77% of theory) melting at 175° C. were obtained. 71.5 g (0.29 mole) of the 5-(β-hydroxyethylsulfonyl)-salicylic acid were then reacted for 5 hours at 70° C. with a mixture of 20 ml (0.29 mole) chlorosulfonic acid and 150 ml anhydrous dioxane, in which reaction hydrogen chloride was split off. The dissolved 5-(β-hydroxysulfonyl-oxy-ethylsulfonyl)-salicylic acid was reacted with a suspension of 91 g (0.5 mole) barium carbonate in 250 ml water (generation of CO2). After filtration, the limpid solution was concentrated by evaporation at 40° C. 120 g of the barium salt of 5-(-hydroxysulfonyloxyethyl-sulfonyl)-salicylic acid (R'--SO2 --CH2CH2 --OSO3Ba/2, R' = barium salicylate) melting at 266° C. remained behind (yield 90% of theory).