Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-])=O)[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[N:16]=2)[N:3]=1>CCO.[OH-].[OH-].[Pd+2]>[CH:21]([C:17]1[N:16]=[C:15]([CH2:14][N:4]2[C:5]3[CH:6]=[CH:7][CH:8]=[C:9]([NH2:11])[C:10]=3[CH:2]=[N:3]2)[CH:20]=[CH:19][CH:18]=1)([CH3:23])[CH3:22]
Reactant: CC(C)c1cccc(Cn2nc(Br)c3c([N+](=O)[O-])cccc32)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1cccc(Cn2ncc3c(N)cccc32)n1
Reaction time: 4 h
Yield: 68 %

Procedure:
To 3-bromo-1-((6-isopropylpyridin-2-yl)methyl)-4-nitro-1H-indazole (2.10 g, 5.60 mmol) in EtOH (30 mL) was added Pd(OH)2/C (1.21 g, 1.72 mmol). The reaction mixture purged with N2 and H2 three times each. The reaction was then charged with H2 to 45 psi. The reaction mixture was stirred for 4 hours and filtered through Celite®. The Celite® was washed with EtOH (200 mL) and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (EtOAc/hexane, 2:1) to give the desired product (68%).
Reaction SMILES: [CH3:1][NH:2][C:3]([O:5][N:6]=[C:7]([S:9][CH3:10])[CH3:8])=[O:4].[CH3:11][O:12][CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[S:16]Cl.C(N(CC)CC)C.S(=O)(=O)(O)O>ClC(Cl)C>[CH3:1][N:2]([S:16][N:15]([CH2:14][CH2:13][O:12][CH3:11])[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:3]([O:5][N:6]=[C:7]([S:9][CH3:10])[CH3:8])=[O:4]
Reactant: COCCN(CCC(=O)OC)SCl
Reactant: CNC(=O)ON=C(C)SC
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: COCCN(CCC(=O)OC)SN(C)C(=O)ON=C(C)SC
Yield: 87.8 %

Procedure:
A 14.6 g (0.09 mole) quantity of S-methyl N-[(methylcarbamoyl)oxy]thioacetimidate was poured into 100 ml of a dichloroethane solution containing 22.75 g (0.1 mole) of N-methoxyethyl-N-methoxycarbonylethylaminosulfenyl-chloride. The mixture was agitated by a stirred and 18 g (0.18 mole) of triethylamine was added dropwise at less than 5° C. over a period of 30 minutes. Thereafter the mixture was agitated at the same temperature for 1 hour. A 5% aqueous solution of sulfuric acid was added to the mixture until a pH of 6 was achieved. The dichloroethane solution was washed with a 5% aqueous solution of sodium hydrogencarbonate and with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated at reduced pressure, giving 31 g of a yellow brown oily product in a yield of 87.8%.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O)[CH3:13]>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][CH2:12][CH3:13])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: CCOc1ccccc1B(O)O
Product: CCOc1ccccc1-c1cccn2nc(Cl)nc12

Procedure:
2-Chloro-8-(2-ethoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine and 2-ethoxyphenylboronic acid in a manner analogous to Example 2c (0.42 g, 71%). MS=274 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:14]([OH:16])=O)=[N:11][NH:12][CH:13]=1.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:14]([C:10]3[C:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])=[CH:13][NH:12][N:11]=3)=[O:16])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1
Reactant: O=C(O)c1n[nH]cc1-c1ccc(Cl)cc1Cl
Reactant: CN1CCN(c2ccc(CN)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(CNC(=O)c3n[nH]cc3-c3ccc(Cl)cc3Cl)cc2)CC1
Yield: 28.3 %

Procedure:
A solution of 4-(2,4-dichloro-phenyl)-1H-pyrazole-3-carboxylic acid (70 mg; 0.27 mmol), 4-(4-methyl-piperazin-1-yl)-benzylamine (62 mg; 0.3 mmol), EDAC (63 mg; 0.33 mmol) and HOBt (45 mg; 0.33 mmol) in 5 ml of DMF was stirred at room temperature for 48 hours. The reaction was evaporated and the residue partitioned between ethyl acetate and brine. The ethyl acetate layer was separated, dried (MgSO4), filtered, evaporated then dried further under vacuum to give 34 mg of 4-(2,4-dichloro-phenyl)-1H-pyrazole-3-carboxylic acid 4-(4-methyl-piperazin-1-yl)-benzylamide. (LC/MS: Rt 2.42 [M+H]+ 444).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH:7]=[CH:8][NH:9]2)=[N:4][CH:3]=1.CN(C=O)C.C(Cl)(=O)C([Cl:21])=O.C(=O)(O)[O-].[Na+]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[CH:7][C:6]=2[Cl:21]
Reactant: O=c1cc[nH]c2cc(Br)cnc12
Reactant: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccnc2cc(Br)cnc12
Temperature: 95 °C
Reaction time: 16 h
Yield: 14 %

Procedure:
7-bromo-1,5-naphthyridin-4(1H)-one (23.8 g, 105.8 mmol), acetonitriel (192 mL, 105.8 mmol), and DMF (2.05 mL, 26.5 mmol) were placed in a 3-necked round bottom flask set up with a reflux condenser. Argon bubbled through. Reaction mixture brought to reflux (˜95° C.). Oxalyl chloride (28.7 ml, 328.1 mmol) was added dropwise via addition funnel over 40 minutes and reaction allowed to stir at this temperature for 16 hrs. Reaction mixture cooled to 0° C. and basified to pH ˜8 with aqueous sodium bicarbonate solution. Product extracted with DCM (500 mL) three times. Organic layers combined, dried over sodium sulfate and concentrated to afford brown solid. This was purified by ISCO silica gel chromatography to afford 3-bromo-8-chloro-1,5-naphthyridine (3.6 g, 14% yield) as fluffy tan solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([N+:10]([O-])=O)[NH:7][N:6]=1)=[O:4]>C(O)(=O)C.O1CCCC1.[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([NH2:10])[NH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1cc([N+](=O)[O-])[nH]n1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)c1cc(N)[nH]n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.4 %

Procedure:
10.25 g (60 mmol) of 5-nitro-1H-pyrazole-3-carboxylic acid methyl ester was dissolved in 75 mL of acetic acid (AcOH) and 75 mL of tetrahydrofuran (THF). After a vacuum and argon cycle, 2.05 g (20% weight) of palladium on carbon (Pd/C 10 wt %) was added, the mixture was degassed again and filled with hydrogen from a balloon. The reaction mixture was stirred at rt under hydrogen atmosphere for 2 days. Analysis by thin layer chromatography (TLC) showed complete conversion of starting material to product. The mixture was then concentrated, the resulting purple colored oil was taken in 300 mL of ether, the finely dispersed purple impurity was filtered off, and the ether filtrate was evaporated to give 7.23 g (85% yield) of 5-amino-1H-pyrazole-3-carboxylic acid methyl ester as an off-white solid as indicated by 1H NMR; whose structure was confirmed using 1H NMR
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9](=[CH2:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C(O)C.[Pd]>[CH3:16][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: C=C(C(=O)OCC)c1cnccc1N(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)c1cnccc1N(C)C
Yield: 85.3 %

Procedure:
To a solution of the product of step (iii) (3.6 g) in absolute ethanol (100 ml) was added 5% palladium/charcoal catalyst, and the mixture hydrogenated at ambient temperature and pressure until the theoretical volume of hydrogen had been consumed. The catalyst was removed by filtration through celite and the filtrate evaporated to yield ethyl 2-(4-dimethylamino-3-pyridyl)propanoate as a pale yellow oil (3.1 g) NMR (d6DMSO): δ1.15 (3H,t); 2.65 (2H,t); 2.8 (6H,s); 2.9 (2H,t); 4.05 (2H,q); 6.8 (2H,d); 8.2 (2H,d); m/e 223 (M+H)+.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[CH3:19][S:20]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)(=[O:22])=[O:21]>>[CH3:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:25][CH:24]=1)(=[O:22])=[O:21]
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: CS(=O)(=O)c1ccc(-c2cc(C#N)cc3cc4n(c23)CCCNC4=O)cc1

Procedure:
The title compound, light grey solid (93 mg, 98%), MS (ISP) m/z=380.3 [(M+H)+], mp 305.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 4-methanesulfonyl-phenylboronic acid (65.0 mg, 0.325 mmol).
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[S:20][C:19]([C:21]([NH:23][CH:24]([CH:30]([CH3:32])[CH3:31])[C:25]([O:27]CC)=[O:26])=[O:22])=[N:18][CH:17]=4)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.O.[OH-].[Li+].Cl>C1COCC1>[F:1][C:2]1[CH:34]=[CH:33][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]4[S:20][C:19]([C:21]([NH:23][CH:24]([CH:30]([CH3:32])[CH3:31])[C:25]([OH:27])=[O:26])=[O:22])=[N:18][CH:17]=4)=[CH:14][CH:15]=3)[S:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)C(NC(=O)c1ncc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)s1)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(NC(=O)c1ncc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)s1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of Ethyl 2-(5-(4-(6-fluorobenzo[d]thiazol-2-ylamino)phenyl)thiazole-2-carboxamido)-3-methylbutanoate (Example 19, 80 mg) in THF (1.6 ml) was added 1 M aqueous solution of Lithium hydroxide monohydrate (0.32 ml) and the mixture was stirred at RT for 4 hours. The reaction mixture was acidified with dilute HCl and extracted with EtOAc. The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure to get yellow solid, which was crystallized in ethyl acetate to give the title compound. Yield: 58 mg (77%); 1HNMR (DMSO-d6, 300 MHz): δ 12.99 (bs, 1H), 10.76 (s, 1H), 8.36 (s, 1H), 8.34 (d, 1H), 7.88 (d, 2H), 7.8 (d, 2H), 7.77 (d, 1H), 7.65 (dd, 1H), 7.2 (m, 1H), 4.32, (m, 1H), 2.27 (m, 1H), 0.97 (d, 6H); MS (ES+): m/z 471 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH3:19][N:20]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:21](Cl)=[O:22]>>[O:11]([CH2:10][C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:21](=[O:22])[N:20]([CH3:19])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:7][CH:6]=1)=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(COc1ccccc1)Nc1ccc(O)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc(NC(=O)COc2ccccc2)cc1)c1ccccc1

Procedure:
The title product was prepared from N-(4-hydroxy-phenyl)-2-phenoxy-acetamide and N-methyl-N-phenylcarbamoyl chloride. The crude product was purified by preparative HPLC (54%, oil). HPLC-MS: m/z=277.2 (M+1); Rt: 4.19 min.
Reaction SMILES: [CH2:1]([N:8]1[C:13]2[CH:14]=[C:15]([CH2:18][C:19]3[CH:24]=[C:23]([C@H:25]4[C@H:30]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C@@H:29]([O:39][CH2:40][C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[C@H:28]([O:47][CH2:48][C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)[C@@H:27]([CH2:55][O:56][CH2:57][C:58]5[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=5)[O:26]4)[CH:22]=[CH:21][C:20]=3Br)[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:65]1(B(O)O)[CH2:67][CH2:66]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([N:8]1[C:13]2[CH:14]=[C:15]([CH2:18][C:19]3[CH:24]=[C:23]([C@H:25]4[C@H:30]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C@@H:29]([O:39][CH2:40][C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[C@H:28]([O:47][CH2:48][C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)[C@@H:27]([CH2:55][O:56][CH2:57][C:58]5[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=5)[O:26]4)[CH:22]=[CH:21][C:20]=3[CH:65]3[CH2:67][CH2:66]3)[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)C1CC1
Reactant: Brc1ccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc2c(c1)N(Cc1ccccc1)CCO2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(COC[C@H]2O[C@@H](c3ccc(C4CC4)c(Cc4ccc5c(c4)N(Cc4ccccc4)CCO5)c3)[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Temperature: 100 °C
Yield: 95 %

Procedure:
To a stirred solution of 4-benzyl-6-[2-bromo-5-((2S,3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine (0.35 g, 0.38 mmol) in toluene:water (10:1 mixture, 10 mL) was added cyclopropylboronic acid (49.2 mg, 0.5731 mmol) tricyclohexylphosphine (26.7 mg, 0.0955 mmol), and potassium phosphate (0.28 g, 1.34 mmol). The reaction mixture was degassed for 45 min then palladium (II) acetate (8.5 mg, 0.03821 mmol) was added. After heating overnight at 100° C., the reaction mixture was cooled to room temperature and water (20 mL) was added. The resulting mixture was extracted with ethyl acetate (2×25 mL), washed with water and brine, then dried over sodium sulfate, concentrated and purified by column chromatography to furnish 4-benzyl-6-[2-cyclopropyl-5-((2S,3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine (317 mg). The product was taken up for the next step without characterization.
Reaction SMILES: C(OC([N:8]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[CH:19][CH:18]=[N:17]2)=[CH:12][CH:11]=1)[NH2:9])=O)(C)(C)C.O1CCOCC1.[ClH:27]>C(Cl)Cl>[ClH:27].[N:16]1([C:13]2[CH:14]=[CH:15][C:10]([NH:8][NH2:9])=[CH:11][CH:12]=2)[CH:20]=[CH:19][CH:18]=[N:17]1
Reactant: CC(C)(C)OC(=O)N(N)c1ccc(-n2cccn2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NNc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Title compound 51A, N-(4-Pyrazol-1-yl-phenyl)-hydrazinecarboxylic acid tert-butyl ester (0.42 g, 1.0 eq, 1.53 mmol) was suspended in a mixture of 4M HCl in Dioxane (6.5 ml, 17.0 eq, 26 mmol) and DCM (5 ml). The mixture was then stirred at room temperature for 24 hours solvent was then removed in vacuo to yield impure title compound. (0.31 g). LCMS: [M+H]+=158/175, 65% purity.
Reaction SMILES: [C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][C:16](N5CCNCC5)=[N:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:27][CH:28]1[O:33][CH:32]([CH3:34])[CH2:31][NH:30][CH2:29]1>>[CH3:34][CH:32]1[O:33][CH:28]([CH3:27])[CH2:29][N:30]([C:16]2[CH:15]=[CH:14][C:13]3[NH:12][CH:11]=[C:10]4[C:25](=[O:26])[N:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[N:8]=[C:9]4[C:18]=3[N:17]=2)[CH2:31]1
Reactant: O=c1c2c[nH]c3ccc(N4CCNCC4)nc3c-2nn1-c1ccccc1
Reactant: CC1CNCC(C)O1
Product: CC1CN(c2ccc3[nH]cc4c(=O)n(-c5ccccc5)nc-4c3n2)CC(C)O1

Procedure:
The title compound was prepared following the procedure described for 6a using 2,6-dimethylmorpholine instead of piperazine. 1H-NMR (DMSO-d6) δ (ppm): 1.19 (6H, d, J=7.05 Hz), 2.36 (2H, t, J=12.09, 10.98 Hz), 3.75 (4H, brm), 7.16 (1H, tt, J=7.42, 1.09 Hz), 7.43 (4H, m), 7.56 (2H, d, J=9.06 Hz), 8.23 (2H, dt, J=8.79, 1.37 Hz), 8.56 (1H, s). m/z 376.5 (MH+).
Reaction SMILES: [K].[CH3:2][CH:3]([N:5]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[NH:7][S:6]1(=[O:17])=[O:16])[CH3:4].[C:18](Cl)(=[O:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[CH3:4][CH:3]([N:5]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[N:7]([C:18](=[O:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[S:6]1(=[O:17])=[O:16])[CH3:2]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CC(C)N1C(=O)c2ccccc2NS1(=O)=O
Agent: [K]
Product: CCCCCCCCCCCC(=O)N1c2ccccc2C(=O)N(C(C)C)S1(=O)=O
Reaction time: 48 h

Procedure:
Following the above procedure 10.0 g of the potassium salt of 3-(1-methylethyl)-1H-2,1,3-benzothiadiazin- -4 (3H)-one-2,2-dioxide was caused to react with 8.9 ml of lauroyl chloride at ca 25° C. After 48 hours, the mixture was filtered and the solvent removed from the filtrate in vacuo to afford 14.1 g of crude product. This was washed with two 50 ml-portions of methanol to afford upon air drying 3-(1-methylethyl)-1-(1-oxododecanyl)-1H-2,1,3-benzothiadiazin-4 (3H)-one-2,2-dioxide, m.p. 57.5°-58.5° C.
Reaction SMILES: [OH-].[Na+].CC1(C)[O:8][CH:7]([CH2:9][OH:10])[CH2:6][O:5]1.[CH2:12](OCC=C)[CH:13]1O[CH2:14]1>CCOCC>[C:13](=[C:9]([CH:7]([CH2:6][OH:5])[OH:8])[OH:10])([CH3:14])[CH3:12]
Reactant: C=CCOCC1CO1
Reactant: CC1(C)OCC(CO)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)=C(O)C(O)CO
Temperature: 80 °C

Procedure:
A catalytic quantity of NaOH (MW 40.00; 0.6 mol-24 g) is added to 1.2-isopropylidene-rac-glycerol (MW 132.16; 16 mol-2115 g), which is rendered a solution by stirring and heating to 80° C. At 80° C., allyl glycidyl ether (MW 114.14; 6 mol-685 g) is added dropwise over a period of 2 hours, and the reaction mixture stirred for another 2 hours at 80° C. By this point in time the epoxide (Rf in ether=0.8) has reacted completely to form the G3 constituent (Rf in ether=0.6) The excess iso-propylidene-rac-glycerol has an Rf of 0.65 in ether and is removed from the reaction mixture at 75° C./10 mbar. The residue has 1 l diisopropyl ether added to it and is extracted twice with 1 l NaCl (1% solution in H2O) in each case. The organic phase is rotated in an evaporator and distilled (Kpi10-1 mbar 125° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([Sn](CCCC)(CCCC)CCCC)=[CH:7][CH:6]=1)[CH3:2].FC(F)(F)S(O[C:31]1[CH:36]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:35][CH2:34][CH2:33][CH:32]=1)(=O)=O>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:6]=[CH:7][C:8]([C:35]2[CH:36]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:31][CH2:32][CH2:33][CH:34]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(=O)OCC)cc1
Reactant: CC(C)(C)C1CCCC=C1OS(=O)(=O)C(F)(F)F
Product: CCOC(=O)c1ccc(C2=CCCCC2C(C)(C)C)cc1
Yield: 66.8 %

Procedure:
4-(Tri-n-butyl-stannyl)-benzoic acid ethyl ester of Example 15, Step A (2.00 g, 4.55 mmol) and 6-tert-butyl-cyclohex-1-en-1-yl trifluoromethanesulfonate (1.43 g, 5.01 mmol) were reacted by the procedure described in Example 15, Step B. Purification by flash column chromatography on silica gel, eluting with a solvent gradient of from 0 to 10% ethyl acetate in hexane followed by recrystallization from methanol (0° C.) afforded the title compound (0.870 g) as white crystals, m.p. 50° C.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Zn]CC)C.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:23][N:22]=[C:21]([CH3:24])[C:20]=2/[CH:25]=[N:26]/[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:23][N:22]=[C:21]([CH3:24])[C:20]=2[CH:25]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])=[CH:15][CH:14]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1/C=N/S(C)(=O)=O
Reactant: C#C[Si](C)(C)C
Agent: CC[Zn]CC
Solvent: Cc1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(C#C[Si](C)(C)C)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(Trimethylsilyl)acetylene (0.6926 mL, 5 mmol) and diethylzinc (1.1M in toluene, 4.54 mL, 5 mmol) were dissolved in toluene (15.5 mL) and stirred for 1 hour at room temperature. Then, N-[1-[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-meth-(E)-ylidene]-methanesulfonamide (1 g, 0.291 mmol) was added and the reaction was heated to 60° C. for 20 hours. The reaction was quenched with H2O and submitted to aqueous workup then purified via silica gel chromatography to yield the title compound which was brought directly to the next step.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:11]=[C:10]([O:12][CH:13]([F:15])[F:14])[N:9]([CH3:16])[N:8]=2)[N:5]=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].S(Cl)([Cl:23])(=O)=O>C(Cl)Cl>[NH2:1][C:2]1[N:6]([C:7]2[C:11]([Cl:23])=[C:10]([O:12][CH:13]([F:14])[F:15])[N:9]([CH3:16])[N:8]=2)[N:5]=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18]
Reactant: Cn1nc(-n2ncc([N+](=O)[O-])c2N)cc1OC(F)F
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: Cn1nc(-n2ncc([N+](=O)[O-])c2N)c(Cl)c1OC(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1.5 g (5.5 mmole) 5-Amino-4-nitro-1-(1-methyl-5-difluoromethoxy-3-pyrazolyl)pyrazole in 30 ml methylene chloride was treated with 0.74 g (5.5 mmole) sulfuryl chloride and the mixture stirred for 10 minutes at room temperature. It was then concentrated and the residue was recrystallised from diisopropyl ether/ethyl acetate. The mother liquor was concentrated and chromatographed (SiO2 /hexane/ethyl acetate 3:1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[CH3:24][N:25](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:21][C:20]([F:23])([F:22])[O:19][C:16]1[CH:17]=[CH:18][C:13]([N:10]2[CH:11]=[N:12][C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:24]#[N:25])=[CH:3][CH:4]=3)=[N:9]2)=[CH:14][CH:15]=1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(Br)cc3)n2)cc1
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 110 °C
Yield: 94 %

Procedure:
In a 250 mL flask, 3-(4-bromophenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (4.00 g, 10.4 mmol) was dissolved in N,N-dimethylformamide (30 mL) under nitrogen atmosphere. Zinc cyanide (1.46 g, 12.4 mmol) and tetrakis(triphenylphosphine) palladium(0) (0.601 g, 0.0500 mmol) were added and the reaction mixture was heated to 110° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water. The aqueous layer was further extracted with ethyl acetate. The combined organics were washed with water and brine, dried over magnesium sulfate and concentrated. Purification by flash column chromatography eluting with 30% ethyl acetate/hexanes gave the title compound as off-white solid (3.40 g, 94%): mp 172-176° C.; 1H NMR (400 MHz, CDCl3): δ 8.60 (s, 1H), 8.31 (d, J=8.8 Hz, 2H), 7.81 (d, J=8.8 Hz, 2H), 7.77 (d, J=8.8 Hz, 2H), 7.41 (d, J=8.8 Hz, 2H); ES+API m/z 331 ([M+H]+).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1.[CH3:15][C:16]([CH3:19])([O-:18])[CH3:17].[K+].[Cl-].[NH4+].C(OCC)C>C1COCC1.O>[C:16]([O:18][C:11](=[O:12])[NH:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:14])[F:13])=[CH:5][CH:6]=1)([CH3:19])([CH3:17])[CH3:15]
Reactant: CC(C)(C)[O-]
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 87.9 %

Procedure:
A solution of 4-(trifluoromethoxy)phenyl isocyanate (9.75 g, 48.0 mMol) in THF (100 mL) was cooled to 0° C., and a 1.0 M THF solution of potassium tert-butoxide (53 mL, 53 mMol) was added dropwise. The mixture was allowed to warm to room temperature, and stirred for 7 hours. The solution was poured into a mixture of saturated ammonium chloride solution (200 mL), and diethyl ether (200 mL). Enough water was added to redissolve the ammonium chloride that had crashed out, the mixture was shaken in a separatory funnel, and the layers were separated. The organic phase was washed with saturated ammonium chloride (100 mL), water (100 mL), brine (100 mL), dried over sodium sulfate, and concentrated in-vacuo. The residue was purified over silica gel, eluting with 10%-20% ethyl acetate/heptane to yield 11.7 g of white solids as product. NMR (500 MHz, DMSO) δ 9.54 (s, 1H), 7.54 (d, 2H, J=7 Hz), 7.23 (d, 2H, J=8 Hz), 1.45 (s, 9H). Yield=88%.