Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]#[CH:10])[CH2:4][CH2:3]1.[F:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[CH:26]=[C:27](I)[S:28][C:21]=12)[NH2:15]>>[F:11][C:12]1[CH:13]=[C:14]([NH2:15])[CH:16]=[CH:17][C:18]=1[O:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[CH:26]=[C:27]([C:10]#[C:9][CH2:8][N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[S:28][C:21]=12
Reactant: C#CCN1CCN(C)CC1
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Product: CN1CCN(CC#Cc2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Temperature: 50 °C
Yield: 77.6 %

Procedure:
Prepared from 1-methyl-4-(prop-2-ynyl)piperazine (26.8 mg, 0.194 mmol) and 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 6, Step A; 50 mg, 0.13 mmol) according to the procedure described for Example 6, Step B, except the reaction was heated at 50° C. for 7 hours. The crude was purified by preparative TLC eluting with 5% MeOH (containing 7N NH3) in CH2Cl2. The product was obtained as a waxy solid (40 mg, 75%). 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J=6 Hz, 1H), 7.58 (s, 1H), 7.03 (m, 1H), 6.53 (m, 3H), 3.86 (br s, 2H), 3.61 (s, 2H), 2.5-2.8 (m, 8H), 2.37 (s, 3H).
Reaction SMILES: CO[CH:3]([O:12]C)[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[N:14]1([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([CH:3]=[O:12])=[CH:11][CH:10]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNC1
Reactant: COC(OC)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=Cc1ccc(CN2CCCC2)cc1
Reaction time: 72 h
Yield: 100 %

Procedure:
To a solution of 4-(dimethoxymethyl)benzaldehyde (25.0 g, 120 mmol), pyrrolidine (10.0 ml, 120 mmol), acetic acid (6.87 ml, 120 mmol) and anhydrous sodium sulfate (34.1 g, 240 mmol) in dichloromethane (300 ml) was added sodium triacetoxyborohydride (38.2 g, 180 mmol), and the mixture was stirred for 3 days. Potassium carbonate was added to the reaction mixture, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by alumina column chromatography (developing solvent; ethyl acetate). 1N Hydrochloric acid (300 ml) was added to the obtained oil, and the mixture was washed with diethyl ether after 2 hrs. The aqueous layer was basified with potassium carbonate, and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by alumina column chromatography (developing solvent; ethyl acetate) to give the title compound (22.7 g).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][OH:7].Br[CH2:9][C:10]#[N:11].CCN(CC)CC>C1COCC1>[OH:7][CH2:6][CH:2]1[CH2:3][CH2:4][CH2:5][N:1]1[CH2:9][C:10]#[N:11]
Reactant: OCC1CCCN1
Reactant: N#CCBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#CCN1CCCC1CO
Yield: 63.9 %

Procedure:
The method follows that of S3 using 2-pyrrolidinemethanol (24.27 g, 0.241 mol), BrCH2CN (31.81 g, 0.265 mol), Et3N (37 mL, 0.265 mol) and dry THF (150 mL). The product was obtained as a straw-coloured oil (21.60 g, 64%) after purification by flash chromatography using ether/CH3OH (19:1). δH (250 MHz; CDCl3); 1.5-2.0 (m, 5H, CH2CH2CH2, CH2CH2CH, OH), 2.7 (m, 1H), 2.85 (m, 1H), 3.05 (m, 1H), 3.45 (2×d, 1H, J=4 Hz and J=11 Hz, 1×CHCH2OH), 3.65 (2×d, 1H, J=4 Hz and 11 Hz, 1×CHCH2OH) and 3.75 (d, 2H, NCH2CN); δC(62.9 MHz; CDCl3); 23.37, 27.45, 40.96, 53.95, 62.43, 63.06 and 115.48(CN); IR υmax/cm−1; 3375 (NH2), 3300 (NH2), 3200 (OH), 2970-2800 (CH2, CH3), 1600, 1475, 1375, 1230 and 1060; FAB MS, m/z(M+H)+ 141.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH3:26])=[C:6]([CH2:12][C:13]2[C:14]([O:22]C(=O)C)=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=[O:17])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH3:26])=[C:6]([CH2:12][C:13]2[C:14]([OH:22])=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=[O:17])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2OC(C)=O)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2O)=C(C)C1=O
Yield: 31.3 %

Procedure:
3-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.036 g, 0.0963 mmol) was dissolved in methanol (2 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (2 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=9:1) and then recrystallized from diisopropyl ether to obtain the titled compound (0.010 g, 0.0301 mmol, 31%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:13])[O:10][CH2:11]C)=[N:6][CH:7]=1.[CH3:14][O-:15].[Na+]>CO>[CH3:14][O:15][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:13])[O:10][CH3:11])=[N:6][CH:7]=1
Reactant: C[O-]
Reactant: CCOC(=O)Nc1cnc(Cl)cn1
Agent: [Na+]
Solvent: CO
Product: COC(=O)Nc1cnc(OC)cn1
Temperature: 100 °C
Yield: 22.01 %

Procedure:
A 20 mL microwave vial was charged with ethyl (5-chloropyrazin-2-yl)carbamate (500 mg, 2.480 mmol) and 22% sodium methoxide in MeOH (10 mL). The tube was sealed and heated to 100° C. for 6 h. The reaction mixture was then concentrated, diluted between DCM and 2N HCl. The layers were separated and the aqueous layer was extracted with DCM (2×). The combined organic layers were washed with 2N HCl, brine, eluted through a phase separator and concentrated to afford methyl (5-methoxypyrazin-2-yl)carbamate as a brown oil (100 mg, 22.01% yield). MS (m/z) 184 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[CH:14][C:13]=2[CH3:20])=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[C:18]([C:16]1[CH:15]=[CH:14][C:13]([CH3:20])=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=2)[CH:17]=1)#[N:19]
Reactant: CCOC(=O)c1ccc(-c2cc(C#N)ccc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(C#N)cc1-c1ccc(C(=O)O)cc1
Reaction time: 18 h
Yield: 87.5 %

Procedure:
A mixture of 5′-Cyano-2′-methyl-biphenyl-4-carboxylic acid ethyl ester (850 mg) and sodium hydroxide (2M, 15 ml) in ethanol (30 ml) was stirred at 20 C for 18 h. The ethanol was then evaporated and the residue acidified. The resulting solid was collected by filtration and was then purified on silica gel. Gradient elution with 0-30% 20:8:1 CH2Cl2/EtOH/NH3 in CH2Cl2 gave the title compound as a white solid (665 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3]/[CH:4]=[CH:5]/[C:6]([O:8]C)=[O:7].[OH-].[Na+].[ClH:13]>CO.O>[ClH:13].[CH3:1][N:2]([CH3:10])[CH2:3]/[CH:4]=[CH:5]/[C:6]([OH:8])=[O:7]
Reactant: COC(=O)/C=C/CN(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)C/C=C/C(=O)O
Temperature: 50 °C
Yield: 51 %

Procedure:
Methyl (2E)-4-(dimethylamino)but-2-enoate (3.4 g, 23.7 mmol) was dissolved in methanol (25 mL). A solution of sodium hydroxide (0.95 g, 23.7 mmol) in water (7 mL) was added, and the mixture was heated to 50° C. for 1 h. The pH was then adjusted to 2 with conc. hydrochloric acid. The solution was concentrated to dryness, and the residue was triturated with ethanol (30 mL). It was filtered, and the solution was concentrated in vacuo. The residue was triturated with 2-propanol, and the precipitate was collected by suction filtration and dried to yield 2.00 g (51%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1.[CH:23]([Sn](CCCC)(CCCC)CCCC)=[CH2:24]>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:18]1([C:4]2[CH:5]=[C:6]([S:8]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)(=[O:10])=[O:9])[CH:7]=[C:2]([CH:23]=[CH2:24])[N:3]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(N3CCCC3)c2)cc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C=Cc1cc(S(=O)(=O)c2ccc(N)cc2)cc(N2CCCC2)n1
Reaction time: 1 h
Yield: 48.6 %

Procedure:
0.38 g (0.001 Mol) 4-(2-Bromo-6-pyrrolidin-1-yl-pyridine-4-sulfonyl)-phenylamine, 0.116 g (0.0001 Mol) Pd(PPh3)4 and 0.292 ml (0.001 Mol) vinyl-tributylstannane were stirred at reflux for 18 h in a mixture of dioxane (10 ml) and 2N Na2CO3 (2 ml). Then the solvent was evaporated, the residue was taken up in ethyl acetate, washed with water and brine and dried over Na2SO4. After chromatography on SiO2 with ethyl acetate hexane 2:3 the product containing fractions were evaporated and the residue taken up in hexane. The suspension was stirred for 1 h and then filtered. The residue on the filter was washed with hexane (10 ml) and dried in a high vacuum. It was obtained 0.16 g (49%) 4-(2-pyrrolidin-1-yl-6-vinyl -pyridine-4-sulfonyl)-phenylamine as a yellow solid; mp.: 181-182° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH:10](=O)[CH:11]=O>CCO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[CH:11][CH:10]=[N:9]2
Reactant: O=CC=O
Reactant: Nc1ccc(Br)cc1N
Solvent: O
Solvent: CCO
Product: Brc1ccc2nccnc2c1

Procedure:
To a solution of 4-bromobenzene-1,2-diamine (4.0 g, 21 mmol) in 60 mL of EtOH was added 40% glyoxal aldehyde (4.1 ml, 32 mmol) solution in water. The resulting mixture was refluxed for 10 hours. The mixture was concentrated in vacuo and the residue was diluted in, 100 mL of EtOAc. The organic solution was washed with 40 mL of satd. NaHCO3 and 40 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silca gel column chromatography (5% EtOAc/hex to EtOAC) to give light yellow solid 6-bromoquinoxaline. MS (ESI, pos. ion) m/z: 208.9 (M+1).
Reaction SMILES: [CH2:1](OC(OCC)OCC)C.[NH2:11][C:12]1[CH:33]=[CH:32][CH:31]=[CH:30][C:13]=1[C:14]([NH:16][C:17]1[CH:18]=[C:19]([CH:26]=[CH:27][C:28]=1[CH3:29])[C:20]([NH:22][CH:23]1[CH2:25][CH2:24]1)=[O:21])=[O:15].C(O)(=O)C>C(O)C>[CH:23]1([NH:22][C:20](=[O:21])[C:19]2[CH:26]=[CH:27][C:28]([CH3:29])=[C:17]([N:16]3[C:14](=[O:15])[C:13]4[C:12](=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:11]=[CH:1]3)[CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccccc1N
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccccc2c1=O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Triethylorthoformate (0.15 ml) was added to a stirred mixture of 3-[(2-aminobenzoyl)amino]-N-cyclopropyl-4-methylbenzamide (0.093 g) and glacial acetic acid (0.017 ml) in ethanol (10 ml). The mixture was heated to 80° C. and stirred for 16 hours. The reaction mixture was evaporated, dissolved in ethyl acetate (50 ml) and washed with a saturated NaHCO3 solution (100 ml). The organic phase was dried over magnesium sulphate, filtered then concentrated in vacuo onto silica gel (0.1 g). The residue was purified by column chromatography (isolute silica 20 g column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using a gradient of 10% iso-propanol/iso-hexane through to 50% iso-propanol/iso-hexane to give the title compound as a white solid (0.062 g); NMR Spectrum: (DMSOd6) 0.55 (m, 2H), 0.68 (m, 2H), 2.14 (s, 3H), 2.84 (m, 1H), 7.52 (d, 1H), 7.62 (t, 1H), 7.78 (d, 1H), 7.84 (d, 1H), 7.89 (m, 2H), 8.21 (m, 1H), 8.30 (s, 1H), 8.41 (d, 1H); Mass Spectrum: M+H+ 320.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[CH:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)[CH:23]=[C:22]([C:36]([F:39])([F:38])[F:37])[N:21]=3)[CH:19]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:39][C:36]([F:37])([F:38])[C:22]1[N:21]=[C:20]([N:18]2[CH:19]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=3)[N:16]=[CH:17]2)[CH:25]=[C:24]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([F:33])([F:35])[F:34])=[CH:30][CH:31]=2)[CH:23]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cn(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(-c2cn(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)c1
Yield: 41.1 %

Procedure:
To a stirred and cooled suspension of N-tert-butyl-3-{1-[6-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (example 293) (0.110 g, 0.19 mmol) in dichloromethane (0.69 mL) was added TFA (4.3 mL) and the reaction mixture was allowed to stir at room temperature for 16 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane/diethyl ether and dried to yield after silica gel column chromatography with heptane/EtOAc and trituration with diethyl ether the title compound as a white solid (0.040 g, 40%). MS (ISP) 513.2 [(M+H)+]; mp>250° C.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](=[O:14])[N:10]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=2)=[CH:4][CH:3]=1>CO.[Pd]>[F:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:9][N:10]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:21])([CH3:20])[CH3:22])[C:11](=[O:14])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccc(F)nc2)ccc1=O
Agent: [Pd]
Solvent: CO
Product: C[Si](C)(C)CCOCN1CC(c2ccc(F)nc2)CCC1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 92.1 %

Procedure:
To a steel bomb, a solution of 6′-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-[3,3′-bipyridin]-6(1H)-one (311 mg, 0.971 mmol) in MeOH (remaining 60% head space) was added followed by addition of Pd—C (207 mg, 0.194 mmol). After degassing with nitrogen stream, the steel bomb was pressurized with hydrogen gas up to 250 psi. The reaction was stirred at room temperature for 20 h. LCMS—0.9 min MH+325.1 (single major). The reaction mixture was filtered off through Celite (washed with EtOAc). The volatile materials were concentrated in vacuo to give crude 5-(6-fluoropyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2-one (290 mg, 0.894 mmol, 92%), which was used for the next step without further purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1>CC(C)=O>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:4]2[CH2:5][CH2:6][O:1][C:2]3[CH:10]=[CH:9][CH:8]=[CH:7][C:3]2=3)=[CH:20][CH:21]=1)([O-:27])=[O:26]
Reactant: c1ccc2c(c1)NCCO2
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(CN2CCOc3ccccc32)cc1
Reaction time: 8 h

Procedure:
To a mixture of 3,4-dihydro-2H-benzo[b][1,4]oxazine (0.500 g, 3.70 mmol) and potassium carbonate (2.56 g, 18.5 mmol) in acetone (25 mL) was added 1-(bromomethyl)-4-nitrobenzene (0.959 g, 4.44 mmol). The mixture was heated to reflux and stirred overnight. After 16 hrs the mixture was concentrated in vacuo, diluted with EtOAc, and washed with water and brine. The organic fraction was dried over Na2SO4, concentrated in vacuo, and the crude residue was purified by silica gel chromatography using 100% Hexanes to 30% Hexanes:EtOAc to afford 4-(4-nitrobenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine as an orange oil. MS found: M+H+=271.1.
Reaction SMILES: [CH3:1][S:2]([CH:4]([C:17]1[CH:21]=[C:20]([Si:22]([CH3:25])([CH3:24])[CH3:23])[O:19][CH:18]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:3].S([O-])(O[O-])(=O)=[O:27].[K+].[K+]>>[CH3:1][S:2]([CH:4]([C:17]1[CH:21]=[C:20]([Si:22]([CH3:23])([CH3:24])[CH3:25])[O:19][CH:18]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:27])=[O:3]
Reactant: O=S(=O)([O-])O[O-]
Reactant: CCCCCCCCCCCCC(c1coc([Si](C)(C)C)c1)S(C)=O
Agent: [K+]
Product: CCCCCCCCCCCCC(c1coc([Si](C)(C)C)c1)S(C)(=O)=O

Procedure:
3-(1-methylsulfinyltridecyl)-5-trimethylsilylfuran is oxidized using potassium peroxymonosulfate to give 3-(1-methylsulfonyltridecyl)-5-trimethylsilylfuran. Oxidizing with singlet oxygen by the procedure of Example 1 gives 4-(1-methylsulfonyltridecyl)-5-hydroxy-2(5H)-furanone.
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH2:26]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:38]([NH2:40])[CH3:39].C1COCC1>>[CH2:38]([NH:40][CH2:26][CH2:25][CH2:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[C:14]2[S:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)(=[O:13])=[O:12])[CH3:39]
Reactant: Cc1ccc(S(=O)(=O)OCCCOc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)cc1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNCCCOc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Temperature: 25 °C
Yield: 70 %

Procedure:
A solution of toluene-4-sulfonic acid 3-[3-(naphthalene-1-sulfonyl)-1H-indazol -5-yloxy]-propyl ester (0.080 mg, 0.15 mmol) in 10 mL of 2.0 M ethylamine/THF (20 mmoles) was stirred at 90° C. for about 2 hours in a sealed tube. After cooling to ambient temperature the reaction mixture was solvent evaporated. It was dissolved in ethyl acetate and washed twice with aqueous sodium bicarbonate. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 0.75% ammonium hydroxide/7.5% methanol in chloroform. Drying at 66° C. in vacuo for 20 minutes yielded ethyl-{3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl}-amine as a light yellow foam (43.0 mg, 70.0%). This was dissolved in methanol and ethereal hydrochloride was added. Concentrating and drying in vacuo at 83° C. for 16 hours gave the hydrochloride as a pale yellow semi-solid (41.7 mg, 62.3%). Mass Spectrum (+EI, [M+H]+) m/z 410; 1HNMR (500 MHz, DMSO-d6): δ14.14-14.18 (br, 1H), 8.74-8.76 (m, 1H), 8.56-8.72 (br, 2H), 8.52 (dd, 1 h, J=7.44 Hz and 1.22 Hz), 8.27 (d, 1H, J=8.29 Hz), 8.03-8.05 (m, 1H), 7.71-7.75 (m, 1H), 7.54-7.65 (m, 3H), 7.29 (d, 1H, J=2.08 Hz), 7.07-7.10 (m, 1H), 4.09-4.12 (m, 2H), 3.03-3.07 (m, 2H), 2.90-2.97 (m, 2H), 2.05-2.12 (m, 2H), 1.15-1.19 ppm (m, 3H). Elemental Analysis for C22H23N3O3S.1.00 mol HCl.1.20 mol H2O: Calcd: C, 56.51; H, 5.69; N, 8.99; Found: C, 56.20; H, 5.36; N, 8.81.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][CH:16]1[C:21](=[O:22])[N:20]2[CH:23]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[C:24](=[O:30])[N:25]([CH:27]([CH3:29])[CH3:28])[CH2:26][CH:19]2[N:18]([S:39]([C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][C:43]=2[Cl:49])(=[O:41])=[O:40])[CH2:17]1>CC(O)=O.CC#N.CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:15][CH:16]2[C:21](=[O:22])[N:20]3[CH:23]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=4)[C:24](=[O:30])[N:25]([CH:27]([CH3:28])[CH3:29])[CH2:26][CH:19]3[N:18]([S:39]([C:42]3[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][C:43]=3[Cl:49])(=[O:41])=[O:40])[CH2:17]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CC(C)N1CC2N(C(=O)C(N)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Solvent: CC(=O)O
Solvent: CO
Solvent: CC#N
Product: CC(C)N1CC2N(C(=O)C(NC3CCN(Cc4ccccc4)CC3)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 121.2 %

Procedure:
115 mg (0.61 mmol) of 1-benzyl-4-piperidone and then 130 mg (4.1 mmol/g) of (polystyrylmethyl)trimethylammonium cyanoborohydride were added to a solution of 100 mg (0.18 mmol) of 3-amino-6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione in 1.2 ml of 5% HOAc/CH3CN and 3 drops of MeOH. The reaction mixture was shaken at room temperature for 18 hours, filtered and concentrated. 160 mg of beige oil were obtained. The crude product was isolated by flash chromatography in a column packed with 4 g of silica gel (elution with 5% MeOH/EtOAc). Concentration of the appropriate fractions resulted in 110 mg (85%) of the above compound in the form of a clear oil. LC/MS (expected, monoisotopic MW=731.19; measured value (M+H)=732.20)
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][CH2:14][C@@H:9]2[CH2:10][C@@H:11]([OH:13])[CH2:12][N:8]2[CH3:6])=[C:18]([CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CCOc1ccc(F)cc1CCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1C[C@H](O)C[C@H]1CCOc1ccc(F)cc1CCc1ccccc1
Yield: 60.6 %

Procedure:
1115 mg of (2R,4R)-1-t-butoxycarbonyl-2-{2-[4-fluoro-2-(2-phenylethyl)-phenoxy]ethyl}-4-hydroxypyrrolidine [prepared as described in step (a) above], 20 ml of tetrahydrofuran and 200 mg of lithium aluminum hydride were allowed to react together and subsequently treated in the same manner as described in step (b) of Example 1. The concentrated substance thus obtained was purified by silica gel column chromatography, using a 5:1 by volume mixture of methylene chloride and methanol as the eluent, to give 540 mg (yield 61%) of the title compound as a colorless solid substance.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:11]([CH:12]=[O:13])=[CH:10][N:9]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:5]2=[N:6][C:7]=1[CH3:8].S(=O)(=O)([OH:24])N.P([O-])(O)(O)=O.[K+].Cl([O-])=O.[Na+]>O.C(OCC)(=O)C.O1CCCC1.C(O)(C)(C)C>[Br:1][C:2]1[N:3]=[C:4]2[C:11]([C:12]([OH:24])=[O:13])=[CH:10][N:9]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:19])[CH3:21])[C:5]2=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc2c(nc1Br)c(C=O)cn2COCC[Si](C)(C)C
Reactant: NS(=O)(=O)O
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: Cc1nc2c(nc1Br)c(C(=O)O)cn2COCC[Si](C)(C)C
Yield: 91.4 %

Procedure:
To a stirred mixture of 2-bromo-3-methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (3.17 g, 8.55 mmol), tert-butanol (10 mL), tetrahydrofuran (10 mL), and water (10 mL) was added sulfamic acid (3.32 g, 34 mmol) and then a solution of potassium dihydrogen phosphate (8.85 g, 65 mmol) and sodium chlorite (1.93 g, 21 mmol) in water (42 mL). After 1 h the mixture was diluted with ethyl acetate, washed once with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 2-bromo-3-methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3.02 g, 91%) as a light yellow solid. This material was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm −0.10 (s, 9H), 0.83 (t, J=8.0 Hz, 2H), 2.69 (s, 3H), 3.55 (t, J=8.0 Hz, 2H), 5.64 (s, 2H), 8.64 (s, 1H), 12.46 (br s, J=9.06 Hz, 1H, —COOH).