Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[SH:2][CH2:3][CH2:4][NH2:5].[C:6]([C:9]1[CH:10]=[C:11]([S:15]([NH2:18])(=[O:17])=[O:16])[S:12][C:13]=1Cl)(=O)[CH3:7].[BH4-].[Na+].Cl>C(O)C>[CH3:7][CH:6]1[C:9]2[CH:10]=[C:11]([S:15](=[O:17])(=[O:16])[NH2:18])[S:12][C:13]=2[S:2][CH2:3][CH2:4][NH:5]1
Reactant: NCCS
Reactant: CC(=O)c1cc(S(N)(=O)=O)sc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC1NCCSc2sc(S(N)(=O)=O)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.4 %

Procedure:
Sodium metal (0.46 g, 0.02 mol) was dissolved in absolute ethanol (50 mL), under a nitrogen atmosphere and 2-mercaptoethylamine (1.55 g, 0.02 mol) was added. After 10 minutes, 4-acetyl-5-chlorothiophene-2-sulfonamide (1.63 g, 0.007 mol) in dry ethanol (70 mL) was added to the reaction and the mixture refluxed for 18 hours. The reaction was cooled to room temperature and sodium borohydride (1.0 g, 0.026 mol) was added. After three hours the reaction mixture was poured into ice water and acidified with 6N HCl. The aqueous solution was extracted with ethyl acetate and the aqueous solution made basic with NaHCO3 and Na2CO3. The product was extracted into ethyl acetate, the extract was dried (Na2SO4), filtered and evaporated. The residue (1.77 g) was crystallized from ethyl acetate-methanol to give analytically pure product (1.58 g, 85%), mp 182°-185° C.
Reaction SMILES: C([O:8][C:9]1[CH:33]=[CH:32][C:31]([CH:34]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][OH:42])[CH2:36][CH2:35]2)=[CH:30][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12])C1C=CC=CC=1>C(OCC)(=O)C.CO.[C].[Pd]>[OH:8][C:9]1[CH:33]=[CH:32][C:31]([CH:34]2[CH2:35][CH2:36][N:37]([CH2:40][CH2:41][OH:42])[CH2:38][CH2:39]2)=[CH:30][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCN(CCO)CC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCN(CCO)CC2)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
To a solution mixture of the obtained methyl 2-(2-(benzyloxy)-5-(1-(2-hydroxyethyl)piperidin-4-yl)benzamido)-4-phenylbenzoate (0.085 g) in ethyl acetate (1.0 mL) and methanol (1.0 mL), 10% palladium-carbon (0.040 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours. To the reaction mixture, 10% palladium-carbon (0.040 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 4 hours. The insoluble substance was removed from the reaction mixture by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-92% chloroform/methanol] to obtain 0.035 g of methyl 2-(2-hydroxy-5-(1-(2-hydroxyethyl)piperidin-4-yl)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][CH2:28][N:29]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:30]1=[O:41])(C(C)(C)C)(C)C.CO>O1CCCC1>[OH:26][CH2:27][CH2:28][N:29]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[C:30]1=[O:41]
Reactant: CC(C)(C)OC(=O)N1CCN(CCO[Si](C)(C)C(C)(C)C)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(CCO)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
A 1.0M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (4.35 ml) was added to a solution of tert-butyl 3-[2-(tert-butyldimethylsilanyloxy)ethyl]-2-oxoimidazolidine-1-carboxylate (1.50 g) in tetrahydrofuran (15 ml), and the mixture was stirred for 1 hour at room temperature. Methanol (1 ml) was added to the reaction solution, and the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1→10:1) to yield tert-butyl 3-(2-hydroxyethyl)-2-oxoimidazolidine-1-carboxylate (940 mg) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:26])C=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=[CH:10][N+:9]=2[O-:26])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccnc1-c1ccc(F)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)c1ccc[n+]([O-])c1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 2-(4-fluorophenyl)pyridin-3-carboxylate (10.5 g.) and MCPBA (12.33 g., 65%) in dichloromethane was stirred at 0° C. for 1 hour and then at ambient temperature for 2 hours. It was then washed with saturated sodium bicarbonate solution (300 ml.), dried and applied directly to a silica flash column which was eluted firstly with ethyl acetate/iso-hexane (1:1), ethyl acetate and ethyl acetate/methanol (9:1) to give 2-(4-fluorophenyl)-3-(methoxycarbonyl)pyridine-1-oxide as a white solid (10.5 g.).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].Cl[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:11]([O:10][C:8]([NH:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5])=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCC(O)CN
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCC(O)CNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 100.7 %

Procedure:
A mixture of 1-amino-2-butanol (5.5 g, 61.8 mmol), benzyl chloroformate (11.5 g, 67.6 mmol) and sodium carbonate (7.16 g, 67.7 mmol) in water (50 mL) was stirred at 0° C. for 3 h. Water (50 mL) was added to the reaction mixture and the product was extracted with methylene chloride (3×20 mL). The methylene chloride extract was dried over Na2SO4 and concentrated. The residue was passed through a short column (SiO2, hexanes: ethyl acetate/10:1; then ethyl acetate) to afford 1-benzyloxycarbonylamino-2-butanol (13.9 g, 100%) as a liquid.
Reaction SMILES: [C:1]1([CH2:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14]3)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:21]([N:23]([CH2:38][CH3:39])[CH2:24][CH2:25][NH:26][C:27]([C:29]1[C:33]([CH3:34])=[C:32]([CH:35]=O)[NH:31][C:30]=1[CH3:37])=[O:28])[CH3:22].N1CCCCC1>C(O)C>[CH2:38]([N:23]([CH2:21][CH3:22])[CH2:24][CH2:25][NH:26][C:27]([C:29]1[C:33]([CH3:34])=[C:32](/[CH:35]=[C:14]2\[C:15](=[O:20])[NH:16][C:17]3[C:13]\2=[CH:12][C:11]([S:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:10])=[O:9])=[CH:19][CH:18]=3)[NH:31][C:30]=1[CH3:37])=[O:28])[CH3:39]
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccccc3)ccc2N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccccc4)cc32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 54.5 %

Procedure:
To a solution of 5-phenylmethanesulfonyl-1,3-dihydro-indol-2-one (100 mg, 0.34 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (92 mg, 0.34 mmol) in ethanol (4 mL) was added piperidine (0.1 mL). The reaction mixture was stirred at 25° C. for three days. An orange solid product was precipitated out, filtered, washed thrice with ethanol, and dried under high vacuum to provide to provide 99 mg (55%) of 2,4-dimethyl-5-[2-oxo-5-phenylmethanesulfonyl-1,2-dihydro-indol-(3Z)-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[N:28]1([CH2:33][C:34]2[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[N:29]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[N:28]1([CH2:33][C:34]2[CH:41]=[CH:40][C:37]([C:38]3[NH:8][C:5]4=[N:6][CH:7]=[C:2]([Br:1])[C:3]([N:12]5[CH2:17][CH2:16][N:15]([CH2:18][C:19]6[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=6)[CH2:14][CH2:13]5)=[C:4]4[N:9]=3)=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[N:29]1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3ccncc3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(Cn2cccn2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: Brc1cnc2[nH]c(-c3ccc(Cn4cccn4)cc3)nc2c1N1CCN(Cc2ccncc2)CC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a mixture of 5-bromo-3-nitro-4-(4-pyridin-4-ylmethyl-piperazin-1-yl)-pyridin-2-ylamine (0.039 g, 0.10 mmol) and EtOH (3.5 ml) was added 4-pyrazol-1-ylmethyl-benzaldehyde (0.024 g, 0.13 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.40 ml, 0.40 mmol). The reaction mixture was stirred at 80° C. for 20 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with a gradient of methanol (2 to 5%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a solid. The title compound was obtained as a white solid after trituration with diethyl ether (0.025 g, 48%); 1H-NMR (500 MHz, DMSO-d6) 2.63 (br s, 4H, piperazine N(CH2)2), 3.61 (s, 2H, NCH2pyridyl), 3.69 (br s, 4H, piperazine N(CH2)2), 5.42 (s, 2H, C6H4CH2N), 6.30 (t, J=2.0 Hz, 1H, pyrazole 4-H), 7.35 (d, J=8.3 Hz, 2H) and 8.14 (d, J=8.2 Hz, 2H) (3,5-C6H4— and 2,6-C6H4—), 7.39 (d, J=5.9 Hz, 2H, pyridine 3-H, 5-H), 7.49 (d, J=1.7 Hz, 1H, pyrazole-H), 7.86 (d, J=2.2 Hz, 1H, pyrazole-H), 8.24 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.54 (d, J=5.9 Hz, 2H, pyridine 2-H, 6-H), 13.50 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](O)(=[O:13])=[O:12])=[C:7]([O:15][CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:18]>ClC(Cl)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([Cl:18])(=[O:13])=[O:12])=[C:7]([O:15][CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(C(C)(C)C)ccc1S(=O)(=O)O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: COc1cc(C(C)(C)C)ccc1S(=O)(=O)Cl
Temperature: 25 °C
Yield: 65.5 %

Procedure:
To cooled (0° C.) solution of 30 (12.0 g; 49.12 mmol) in dichloroethane (200 mL) was added phosphorus pentachloride (20.5 g; 98.24 mmol) slowly and portion-wise. After addition was complete, the reaction was heated at reflux overnight, cooled to room temperature, and then concentrated under reduced pressure. The resulting crude residue was purified by automated silica gel column chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 50% v/v over 400 mL gradient elution) to give the title product as a dark solid (8.45 g; 65% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:3]=1[O:4][CH2:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[CH:8]([OH:11])[C:9]#[N:10].Cl.[OH2:22]>C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:3]=1[O:4][CH2:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[CH:8]([OH:11])[C:9]([NH2:10])=[O:22]
Reactant: Cc1ccc(C)c(OCc2ccccc2C(O)C#N)c1
Reactant: O
Agent: Cl
Solvent: Cc1ccccc1C
Product: Cc1ccc(C)c(OCc2ccccc2C(O)C(N)=O)c1
Temperature: 50 °C
Yield: 65.7 %

Procedure:
To 10.0 g of 2-(2,5-dimethylphenoxymethyl)-mandelonitrile (content: 96% by weight), 30 g of xylene, 3.66 g of hydrogen chloride and 0.648 g of water were added. The obtained mixture was heated to 50° C., stirred and maintained at the same temperature for 3 hours to obtain a xylene solution containing 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-hydroxyacetamide (yield: 65.7%). The formation of by-products generated by the hydrolysis of 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-hydroxyacetamide was not recognized.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@@:8]2([CH3:16])[NH:14][C:13](=[O:15])[CH2:12][CH2:11][O:10][CH2:9]2)[CH:7]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[C:54](=[NH:67])([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[C:54](=[N:67][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@@:8]2([CH3:16])[NH:14][C:13](=[O:15])[CH2:12][CH2:11][O:10][CH2:9]2)[CH:7]=1)([C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: C[C@@]1(c2cc(Br)ccc2F)COCCC(=O)N1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: C[C@@]1(c2cc(N=C(c3ccccc3)c3ccccc3)ccc2F)COCCC(=O)N1
Temperature: 105 °C

Procedure:
Under an argon atmosphere a mixture of the crude (R)-3-(5-bromo-2-fluoro-phenyl)-3-methyl-[1,4]oxazepan-5-one (626 mg, 1.2 mmol), sodium tert-butoxide (356 mg, 3.59 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (52.4 mg, 0.12 mmol), tris(dibenzylideneacetone)-dipalladium(0) chloroform adduct (38.3 mg, 0.036 mmol), and benzophenonimine (447 mg, 2.4 mmol) in toluene (15 ml) was heated at 105° C. for 16 hours in a sealed vial. For the workup, the reaction mixture was cooled to room temperature, evaporated at reduced pressure, and purified by chromatography on Silicycle-Si-amine column using a gradient of heptane and ethyl acetate=100/0 to 10/20 as the eluent. (R)-3-[5-(Benzhydrylidene-amino)-2-fluoro-phenyl]-3-methyl-[1,4]oxazepan-5-one (intermediate C12A) was obtained as a light yellow foam (348 mg, 69% of theory). MS (ISP): m/z=403.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([N:20]3[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]3)[CH:11]=2)=[CH:4][C:3]=1[NH:27][C:28]([N:30]1[C:34]2[N:35]=[CH:36][N:37]=[C:38](Cl)[C:33]=2[CH:32]=[CH:31]1)=[O:29].C(Cl)(=O)C.[OH:44][CH:45]([C:47]1[CH:48]=[C:49]([CH:51]=[CH:52][CH:53]=1)[NH2:50])[CH3:46]>C(O)CCC>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([N:20]3[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]3)[CH:11]=2)=[CH:4][C:3]=1[NH:27][C:28]([N:30]1[C:34]2[N:35]=[CH:36][N:37]=[C:38]([NH:50][C:49]3[CH:51]=[CH:52][CH:53]=[C:47]([CH:45]([OH:44])[CH3:46])[CH:48]=3)[C:33]=2[CH:32]=[CH:31]1)=[O:29]
Reactant: CC(O)c1cccc(N)c1
Reactant: Cc1cn(-c2cc(C(=O)Nc3ccc(C)c(NC(=O)n4ccc5c(Cl)ncnc54)c3)cc(C(F)(F)F)c2)cn1
Solvent: CCCCO
Solvent: CC(=O)Cl
Product: Cc1cn(-c2cc(C(=O)Nc3ccc(C)c(NC(=O)n4ccc5c(Nc6cccc(C(C)O)c6)ncnc54)c3)cc(C(F)(F)F)c2)cn1
Temperature: 80 °C
Reaction time: 24 h
Yield: 50.7 %

Procedure:
4-Chloro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid {2-methyl-5-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzoylamino]-phenyl}-amide resin (50 mg, 0.05 mmol), prepared as in reference 3, in n-butanol (2 mL) is mixed with acetyl chloride (17.8 μL, 0.25 mmol) and 3-(1-hydroxyethyl)aniline (34 mg, 0.25 mmol) and shaken at 80° C. for 24 hours. The resulting mixture is filtered and the resin is treated with TFA/CH2Cl2/H2O (45/50/5) (600 μL) for 30 minutes before filtering and washing with CH2Cl2 (3×2 mL), MeOH (3×2 mL). The washes are then combined together with n-butanol and concentrated. The residue is purified by preparative HPLC-MS to give 4-[3-(1-hydroxy-ethyl)-phenylamino]-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid {2-methyl-5-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-benzoylamino]-phenyl}-amide (16.6 mg, yield 51%); 1HNMR (400 MHz, DMSO-d6) δ 11.60 (s, 1H), 10.68 (s, 1H), 9.85 (s, 1H), 9.62 (s, 1H), 8.62 (s, 1H), 8.57 (s, 1H), 8.54 (s, 1H), 8.47 (s, 1H), 8.43 (s, 1H), 8.17 (s, 1H), 7.85 (d, J=4.1 Hz, 2H), 7.70 (s, 1H), 7.61 (dd, J=6.5, 8.2 Hz, 1H), 7.35 (d, J=2.3 Hz, 1H), 7.33 (t, J=7.8 Hz, 1H), 7.09 (s, 1H), 7.08 (d, J=6.8 Hz, 1H), 4.75 (q, J=6.4 Hz, 1H), 2.47 (s, 3H), 2.36 (s, 3H), 1.36 (d, J=6.4 Hz, 3H); ESIMS m/z 655.2 (M++1).
Reaction SMILES: [O:1]=[S:2]1(=[O:32])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:31])[N:14]([N:23]=[CH:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:32]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:31])[N:14]([NH:23][CH2:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1
Reactant: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1N=Cc1cccnc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1NCc1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 266A (0.062 g, 0.14 mmol) in tetrahydrofuran (2.5 mL) and methanol (0.012 mL, 0.280 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.105 mL, 0.210 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of approximately 2-4, diluted with water (8.0 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with methanol/diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.99 (s, 2 H) 6.22 (t, J=6.62 Hz, 1 H) 7.08 (t, J=7.35 Hz, 1 H) 7.27 (m, 2 H) 7.40 (dd, J=7.54, 4.96 Hz, 1 H) 7.54 (m, 2 H) 7.68 (d, J=8.09 Hz, 2 H) 7.93 (m, 1 H) 8.08 (dd, J=7.72, 1.47 Hz, 1 H) 8.51 (dd, J=4.78, 1.47 Hz). (ESI−) m/z 446 (M−H)
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([CH3:11])[C:8]([C:12]2[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=2[F:20])=[C:7]([CH2:21][CH:22]([CH3:25])[CH2:23][CH3:24])[N:6]=1)(=O)=O.[C-:26]#[N:27].[K+]>C(#N)C>[C:26]([C:5]1[N:10]=[C:9]([CH3:11])[C:8]([C:12]2[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=2[F:20])=[C:7]([CH2:21][CH:22]([CH3:25])[CH2:23][CH3:24])[N:6]=1)#[N:27]
Reactant: [C-]#N
Reactant: CCC(C)Cc1nc(S(C)(=O)=O)nc(C)c1-c1c(F)cc(F)cc1F
Agent: [K+]
Solvent: CC#N
Product: CCC(C)Cc1nc(C#N)nc(C)c1-c1c(F)cc(F)cc1F
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A mixture of 0.4 g (1 mmol) of 2-methylsulfonyl-4-methyl-5-(2,4,6-trifluorophenyl)-6-(2-methylbutyl)pyrimidine (Example 1.3.) and 0.2 g (3 mmol) of potassium cyanide in 20 ml of acetonitrile p.a. was stirred at 20° C. for about 16 hours. The reaction mixture was then concentrated, the residue was taken up in methylene chloride and the organic phase was extracted with water. The organic phase was concentrated and the residue was purified by column chromatography using cyclohexane/methyl t-butyl ether mixtures. This gave 0.3 g (94%) of the title compound as a colorless oil.
Reaction SMILES: [Br:1][CH2:2][C:3]([OH:5])=O.[CH2:6]([CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N=C=NC(C)C)(C)C>>[CH2:6]([CH:13]1[CH2:18][CH2:17][N:16]([C:3](=[O:5])[CH2:2][Br:1])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C(O)CBr
Agent: CC(C)N=C=NC(C)C
Product: O=C(CBr)N1CCC(Cc2ccccc2)CC1

Procedure:
Prepared as stated above for compound (22) from bromo acetic acid (935mg, 6.78 mmol) and 4-benzyl piperdine (1.02 g, 5.82 mmol) and diisopropylcarbodiimide (856 mg, 6.78 mmol) to afford compound 23, 1.53 g, (89%), (MH+) m/z 297.88.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([S:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:47]1[NH:52][CH2:51][CH2:50][N:49]2[CH2:53][CH2:54][CH2:55][C@H:48]12.CN(C)C(=O)C>CC1CCCO1>[Cl:11][C:9]1[CH:10]=[C:2]([Cl:1])[C:3]([C:4]([N:52]2[CH2:51][CH2:50][N:49]3[CH2:53][CH2:54][CH2:55][C@@H:48]3[CH2:47]2)=[O:6])=[CH:7][C:8]=1[S:12]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])(=[O:14])=[O:13]
Reactant: C1C[C@@H]2CNCCN2C1
Reactant: O=C(O)c1cc(S(=O)(=O)Nc2ccccc2F)c(Cl)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC1CCCO1
Solvent: CC(=O)N(C)C
Product: O=C(c1cc(S(=O)(=O)Nc2ccccc2F)c(Cl)cc1Cl)N1CCN2CCC[C@@H]2C1
Reaction time: 0.75 h

Procedure:
To 2,4-dichloro-5-{[(2-fluorophenyl)amino]sulfonyl}benzoic acid (800 mg, 2.197 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (919 mg, 2.416 mmol) in 2-methyltetrahydrofuran (15 mL) was added (R)-octahydropyrrolo[1,2-α]pyrazine (388 mg, 3.08 mmol). The reaction was stirred at room temperature for 45 minutes at which time N,N-dimethylacetamide (1 mL) was added. The reaction was stirred for an additional 45 minutes and N,N-dimethylacetamide (3 mL) was added. The reaction was stirred for an addition 2.5 hours, diluted with 2-methyltetrahydrofuran (15 mL), and washed with a solution of 6% sodium bicarbonate and 6% brine (2×15 mL). The aqueous layers were combined and re-extracted with 2-methyltetrahydrofuran (15 mL). The organic layer was washed with saturated brine (4×25 mL), dried over MgSO4, and concentrated. The residue was taken up in ethanol (20 mL) and reconcentrated to give the title compound.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[N:14]2[C:15]3[C:20]([NH:21][C:22](=[O:23])[C:13]2=[N:12][N:11]=1)=[CH:19][C:18]([C:24]([F:27])([F:26])[F:25])=[C:17]([N+:28]([O-])=O)[CH:16]=3)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]>C(O)C.[Ni]>[NH2:28][C:17]1[CH:16]=[C:15]2[C:20]([NH:21][C:22](=[O:23])[C:13]3[N:14]2[C:10]([CH2:9][P:4]([O:3][CH2:1][CH3:2])([O:6][CH2:7][CH3:8])=[O:5])=[N:11][N:12]=3)=[CH:19][C:18]=1[C:24]([F:25])([F:26])[F:27]
Reactant: CCOP(=O)(Cc1nnc2c(=O)[nH]c3cc(C(F)(F)F)c([N+](=O)[O-])cc3n12)OCC
Agent: [Ni]
Solvent: CCO
Product: CCOP(=O)(Cc1nnc2c(=O)[nH]c3cc(C(F)(F)F)c(N)cc3n12)OCC
Yield: 79.5 %

Procedure:
A solution of 1-[(diethoxyphosphoryl)methyl]-8-nitro-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-one (3.25 g, 7.2 mmol) in 500 ml of ethanol was hydrogenated at 40 psi and room temperature for 6 h in the presence of Raney-Ni. The catalyst and precipitated solid was isolated by filtration and washed with ethanol. The ethanolic filtrate was discharged, and the filter-cake was washed with N,N-dimethylformamide. The filtrate was evaporated, and the residue was triturated with water to give the title compound as a light yellow solid (2.4 g, 80%), m.p. 260°-263° C.; 1H-NMR (DMSO-d6): δ 1.18 (t, 6H), 4.07 (quint, 4H), 4.13 (d, 2H), 5.74 (br s, 2H), 7.42 (s, 1H), 7.69 (s, 1H), 11.8 (s, 1H).