Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([N:4]1[CH2:13][CH2:12][C@@:11]2([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[C@@H:6]([CH2:7][CH2:8][C:9](=O)[CH2:10]2)[CH2:5]1)[CH3:3].Cl.[NH2:24][OH:25]>CO>[CH2:2]([N:4]1[CH2:13][CH2:12][C@@:11]2([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[C@@H:6]([CH2:7][CH2:8][C:9](=[N:24][OH:25])[CH2:10]2)[CH2:5]1)[CH3:3]
Reactant: NO
Reactant: CCN1CC[C@]2(c3cccc(OC)c3)CC(=O)CC[C@H]2C1
Agent: Cl
Solvent: CO
Product: CCN1CC[C@]2(c3cccc(OC)c3)CC(=NO)CC[C@H]2C1
Yield: 96.6 %

Procedure:
0.5 g (1.54 mmol) of (±)-trans-2-ethyl-4a-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline hydrochloride, 0.456 g (6.56 mmol) of hydroxylamine hydrochloride and 0.64 g of KHCO3 in 10 ml of MeOH were refluxed for 45 min. The precipitate was filtered, the solvent was removed in vacuo and the residue taken up in H2O. The pH was adjusted to 8 with conc. NH4OH, the aqueous layer was extracted with CH2Cl2. The organic layer was dried, the solvent removed in vacuo, obtaining 0.45 g of the title compound which was used as such in the subsequent step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[C:22]=3[Cl:28])=[O:20])=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].C(O)=[O:34].O.C(=O)(O)[O-].[Na+]>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([OH:34])[C:22]=3[Cl:28])=[O:20])=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:29]([F:30])([F:31])[F:32]
Reactant: O=C(c1ccnc(Cl)c1Cl)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(c1ccnc(O)c1Cl)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A 1 dram vial was charged with 4-chloro-N-[5-chloro-2-(2,3-dichloro-pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (15 mg, 0.028 mmol), formic acid (0.39 mL) and water (0.13 mL). The heterogeneous solution was warmed to 100° C. and stirred overnight. The following day, starting material remained; therefore, an additional 0.26 mL of formic acid was added. The reaction was subsequently warmed to 110° C. and stirred overnight. The resultant mixture was neutralized with saturated aqueous sodium bicarbonate, diluted with EtOAc, and the organic layer washed with saturated sodium bicarbonate. The combined organics were dried with sodium sulfate, concentrated in vacuo, and purified via automated silica gel chromatography to afford the desired hydroxypyridine: 1H NMR (400 MHz, CD3OD) δ 8.26-8.38 (m, 1 H), 8.17-8.20 (m, 2 H), 8.02-8.07 (m, 1 H), 7.72-7.76 (m, 1 H), 7.34-7.37 (m, 1 H), 6.17-6.20 (m, 1 H); MS (ES) (M+H)+ expected 525.9, found 525.9.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([N:20]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)C(=O)OC(C)(C)C)[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][CH2:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:34][CH:35]=3)[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(C(F)(F)F)cc1)C1CCN(C[C@@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@]1(CN2CCC(NCCc3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 12.5 %

Procedure:
Tert-butyl (S)-[1-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperidin-4-yl]-N-[2-(4-trifluoromethylphenyl)ethyl]carbamate prepared in Example 284 (0.196 g, 0.354 mmol) was dissolved in methylene chloride (2 ml). To the solution, trifluoroacetic acid (1 ml) was added followed by stirring at room temperature for 4 hours. To the reaction mixture, a saturated sodium hydrogencarbonate solution was added, and the solution was extracted with methylene chloride twice. The organic phases were combined, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=10/1) and treated with isopropyl ether to afford (S)-N-[1-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperidin-4-yl]-2-(4-trifluoromethylphenyl)ethylamine (0.020 g, yield 12%) as a light yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:11]2[CH2:13][O:12]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:22][C@@H:23]([CH3:29])[C:24]([NH:26][CH2:27][CH3:28])=[O:25]>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[CH2:9][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@H:11]([OH:12])[CH2:13][NH:22][C@@H:23]([CH3:29])[C:24]([NH:26][CH2:27][CH3:28])=[O:25]
Reactant: CCNC(=O)[C@H](C)N
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1
Product: CCNC(=O)[C@H](C)NC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C

Procedure:
Following the general procedure of EXAMPLEs 4 and 14-164 and making non-critical variations and reacting tert-butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE 3) with (2S)-2-amino-N-ethylpropanamide (VI), the title compound is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CS([C:20]1[N:25]=[CH:24][C:23]2=[CH:26][CH:27]=[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])[N:22]2[N:21]=1)=O.[F-].[Cs+].C(N(CC)C(C)C)(C)C>C(O)(C)(C)C>[OH:16][CH2:15][CH2:14][N:11]1[CH2:10][CH2:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:20]3[N:25]=[CH:24][C:23]4=[CH:26][CH:27]=[C:28]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[N:35]([CH3:40])[S:36]([CH3:39])(=[O:38])=[O:37])[N:22]4[N:21]=3)=[CH:7][CH:6]=2)[CH2:13][CH2:12]1
Reactant: Nc1ccc(N2CCN(CCO)CC2)cc1
Reactant: CN(c1ccccc1-c1ccc2cnc(S(C)=O)nn12)S(C)(=O)=O
Agent: [Cs+]
Agent: [F-]
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ccccc1-c1ccc2cnc(Nc3ccc(N4CCN(CCO)CC4)cc3)nn12)S(C)(=O)=O
Temperature: 120 °C

Procedure:
Into a 8-dram vial, 2-[4-(4-Amino-phenyl)-piperazin-1-yl]-ethanol (0.134 g, 0.604 mmol), N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (0.100 g, 0.274 mmol), Cesium fluoride (0.104 g, 0.686 mmol), N,N-Diisopropylethylamine (0.1051 mL, 0.6036 mmol) and tert-Butyl alcohol (1.50 mL) were added. The reaction was heated at 120° C. overnight. LCMS suggested presence of desired product. The solvent was removed under vacuum. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give N-[2-(2-{4-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-phenylamino}-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide as a yellow solid (48 mg, 34%). LCMS (E/I+) 522.16 (M+H). NMR 1H (DMSO-d6)-9.15 (bs, 1H), 9.24 (s, 1H), 8.94 (s, 1H), 8.02 (d, 1H, J=7.91 Hz), 7.66 (d, 1H, J=7.34 Hz), 7.47-7.62 (m, 4H), 6.98 (d, 1H, J=4.52 Hz), 6.93 (d, 1H, J=4.52), 6.87 (d, 1H, J=8.47 Hz), 3.77 (bs, 2H), 3.70 (d, 2H, J=12.98 Hz), 3.58 (d, 2H, J=12.86 Hz), 3.13-3.30 (m, 2H), 3.08 (s, 1H), 2.97 (t, 2H, J=12.42 Hz), 2.89 (s, 3H).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:22][NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>>[CH3:22][N:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: CNc1ccccc1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ncc(F)nc34)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: CN(c1ccccc1)c1cnc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1
Temperature: 0 °C
Yield: 46 %

Procedure:
Prepared similarly to that described in Example 210 using 2-(3-fluoroquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 210i; 56 mg, 0.198 mmol), N-methylaniline (150 μl, 1.389 mmol, Alfa Aesar, Ward Hill, Mass.), and NaHMDS (1.0M in THF; 1389 μl, 1.389 mmol) and heating at 0° C. for 1 h. Purification by silica gel (100% DCM to 3% MeOH/DCM) provided 2-(3-(methyl(phenyl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (46% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.76 (t, J=6.94 Hz, 2H) 3.33 (s, 3H) 3.42 (td, J=6.80, 2.45 Hz, 2H) 6.97 (br. s., 1H) 7.15 (d, J=2.15 Hz, 1H) 7.41-7.49 (m, 2H) 7.50-7.55 (m, 2H) 7.56-7.62 (m, 2H) 7.70 (dd, J=8.02, 1.17 Hz, 1H) 8.01 (dd, J=7.53, 1.27 Hz, 1H) 8.45 (s, 1H) 11.70 (br. s., 1H). MS (ESI, pos. ion) m/z: 370.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][CH:7]=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH2:22][CH2:23][CH2:24][F:25]>C(#N)C>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]([CH2:21][CH2:22][CH2:23][CH2:24][F:25])[CH:7]=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1
Reactant: FCCCCBr
Reactant: O=S1(=O)N=CNc2ccc(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=S1(=O)N=CN(CCCCF)c2ccc(Cl)cc21
Temperature: 100 °C

Procedure:
150 mg of the compound obtained in Step A of Example 1 are dissolved in 8 ml of acetonitrile, to which 300 mg of K2CO3 and 0.15 ml of 1-bromo-4-fluorobutane are added. The reaction mixture is introduced into a sealed autoclave and is heated at 100° C. for 3 hours. After cooling, the solvent is evaporated off under reduced pressure and the residue is taken up in a minimum of water. The insoluble material is collected by filtration, washed with water and dried. The precipitate is then recrystallised from a minimum of ethyl acetate with the aid of heat. After cooling, the title compound is collected by filtration, washed with a minimum of ethyl acetate and dried.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Cl[C:6]1[S:7][C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=1>C(#N)C>[CH3:2][CH:1]([NH:4][C:6]1[S:7][C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]([C:11]([F:13])([F:12])[F:14])[N:10]=1)[CH3:3]
Reactant: CC(C)N
Reactant: CCOC(=O)c1sc(Cl)nc1C(F)(F)F
Solvent: CC#N
Product: CCOC(=O)c1sc(NC(C)C)nc1C(F)(F)F
Yield: 42.2 %

Procedure:
By the procedure of Example 39, a stirred mixture of 10 ml acetonitrile, 2.28 g (38.6 mmol) of iso-propylamine, and 5 g (19.3 mmol) of ethyl 2-chloro-4-trifluoromethyl-5-thiazolecarboxylate (prepared as described in U.S. Pat. No. 4,199,506), was heated at reflux for 16 hours. The product was separated and then recrystallized in hexane to yield 2.30 g of a beige solid product (m.p.=94°-97° C.) identified in Table 1.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:18])[C@@H:12]2[C@@H:15]([OH:17])[CH3:16])[C:9]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])(=[O:3])[CH3:2].Cl[Si:33]([CH3:36])([CH3:35])[CH3:34]>N1C=CC=CC=1>[C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:18])[C@@H:12]2[C@@H:15]([O:17][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH3:16])[C:9]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)Cl
Reactant: CC(=O)NCCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@H](C)O)[C@H]2C1
Solvent: c1ccncc1
Product: CC(=O)NCCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@H](C)O[Si](C)(C)C)[C@H]2C1

Procedure:
p-Nitrobenzyl (5R,6S)-3-(2-acetamidoethylthio)-6-[(1S)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (250 mg) in pyridine (7 ml) were treated with 70 mg. aliquots of chlorotrimethylsilane until all the starting hydroxycompound has reacted (4 aliquots required). The pyridine was removed by evaporation in vacuo, ethyl acetate (20 ml) was added to the residue and the resultant solution washed with water (20 ml). The ethyl acetate was dried (MgSO4) and evaporated in vacuo. Toluene (20 ml) was added to the residue and evaporated in vacuo to remove residual traces of pyridine. The crude silyl ether was then chromatographed on silica gel (0.040-0.063 mm; 15 g) eluting with ethyl acetate. Fractions containing the trimethylsilyl ether were combined and evaporated in vacuo to yield p-nitrobenzyl (5R, 6S)-3-(2-acetamidoethylthio)-6-[(1S)-1-trimethylsilyloxyethyl]7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (145 mg). Found M+ m/e 521.1657 C23H31N3O7SSi requires m/e 521.1650.
Reaction SMILES: [CH:1]([C:3]([CH3:5])=[O:4])=[CH2:2].O.[CH:7]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:11][CH2:10]1)=O.[OH-].[K+]>C(O)C>[O:4]=[C:3]1[CH2:5][CH2:7][C:9]2([CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])[CH2:11][CH2:10]2)[CH:2]=[CH:1]1
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: C=CC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C1C=CC2(CC1)CCN(C(=O)OCc1ccccc1)CC2

Procedure:
Methyl vinyl ketone (1.64 ml), ethanol (5 ml) and water (5 ml) were added to benzyl 4-formylpiperidine-1-carboxylate (5 g). The mixture was then added to a boiling solution of potassium hydroxide (0.22 g) in ethanol (10 ml) and the resulting reaction mixture was refluxed for 1 h (TLC control). When the reaction was complete, the mixture was added to water (25 ml) and extracted with ethyl acetate (2×50 ml). The combined organic phases were dried (Na2SO4) and concentrated in vacuo. The crude product obtained in this way was purified by column chromatography (silica gel, 25% ethyl acetate/hexane). Yield: 2.8 g (46%)
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:40]1[N:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.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>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:40]5[CH:41]=[CH:42][C:43]([CH3:46])=[CH:44][N:45]=5)=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
Reactant: Cc1ccc(Br)nc1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)nc1
Temperature: 25 °C
Yield: 20.5 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 6-bromo-3-picoline (344 mg, 2 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 100° C. for 1 h under microwave irradiation. The reaction mixture was cooled to room temperature and purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (107 mg, 21%) as a yellow oily substance.
Reaction SMILES: [CH2:1]([S:3]([NH:6][C@@H:7]([CH:11]([CH3:13])[CH3:12])[C:8]([OH:10])=O)(=[O:5])=[O:4])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][NH2:45])=[CH:39][C:38]=1[O:46][CH3:47])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl>O1CCCC1>[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][NH:45][C:8](=[O:10])[C@@H:7]([NH:6][S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH:11]([CH3:13])[CH3:12])=[CH:39][C:38]=1[O:46][CH3:47])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCS(=O)(=O)N[C@H](C(=O)O)C(C)C
Reactant: COc1cc(CCN)ccc1OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCS(=O)(=O)N[C@H](C(=O)NCCc1ccc(OCc2ccccc2)c(OC)c1)C(C)C
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
21.1 g of (S)-2-(ethylsulfonylamino)-3-methyl-butyric acid and 12 ml of N-methylmorpholine are cooled in 450 ml of tetrahydrofuran, with stirring, to −20° C. 13.2 ml of chloroformic acid isobutyl ester are added dropwise thereto over 10 min and the reaction mixture is subsequently stirred for 1 hour at −10° C. It is then cooled to −20° C. and a solution of 26.1 g of 2-(4-benzyloxy-3-methoxyphenyl)-ethylamine in 100 ml of tetrahydrofuran is added dropwise over 20 min. The reaction mixture is then stirred for 4 hours without cooling, the internal temperature gradually rising to room temperature. The reaction mixture is introduced into 400 ml of 2N hydrochloric acid and extracted twice with 500 ml of ethyl acetate each time. The organic phases are washed once with 250 ml of 2N hydrochloric acid, once with 250 ml of saturated sodium chloride solution, twice with 250 ml of 2N potassium hydrogen carbonate solution each time and once with 250 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated, yielding (S)-2-(ethylsulfonylamino)-3-methyl-butyric acid N-[2-(4-benzyloxy-3-methoxyphenyl)-ethyl]-amide, which can be purified by recrystallisation from tert-butyl methyl ether, m.p. 140-142° C.
Reaction SMILES: [OH-].[K+].[CH3:3][CH:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[N:9]1[C:13]([NH2:14])=[C:12]([C:15]#[N:16])[C:11]([CH3:17])=[N:10]1.OO.C([OH:22])C>O.CO>[CH3:3][CH:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[N:9]1[C:13]([NH2:14])=[C:12]([C:15]([NH2:16])=[O:22])[C:11]([CH3:17])=[N:10]1
Reactant: Cc1nn(C2CCCC2C)c(N)c1C#N
Reactant: CCO
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nn(C2CCCC2C)c(N)c1C(N)=O
Temperature: 25 °C
Yield: 84 %

Procedure:
85% Potassium hydroxide (5.8 g, 88.5 mmol) was dissolved in water (50 ml) and the solution was cooled in an ice bath for 1 hour. The 1-(2-methylcyclopentyl)-3-methyl-5-amino-1H-pyrazole-4-carbonitrile (2.6 g, 12.7 mmol) in methanol (5.0 ml)/water (25 ml) was then added, followed by 30% hydrogen peroxide (6.5 ml, 63.2 mmol). The reaction mixture was stirred with ice-bath cooling for 4 hours, then was warmed slowly to room temperature. Ethanol was added to the reaction mixture to completely dissolve the starting material and the mixture was stirred at room temperature for 60 hours. The ethanol was removed in vacuo and the oily residue was extracted with ethyl acetate (3×100 ml). The combined organic layers were dried over anhydrous MgSO4 and the solvents were removed in vacuo to afford an amber solid. Recrystallization from acetonitrile and air drying then afforded 2.4 g (84%) of 1-(2-methylcyclopentyl)-3-methyl-5-amino- 1H-pyrazole-4-carboxamide as an off-white solid, m.p. 124°-126° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>O1CCCC1>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])(=[O:12])=[O:13])=[CH:9][CH:10]=1
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(S(=O)(=O)NCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CN(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (1.56 g of a 50 % oil dispersion, 33.0 mmol) is suspended in tetrahydrofuran (85 mL). To this is added a solution of N-[4-methoxybenzenesulfonyl]benzylamine (9.0 g, 32.5 mmol) also in tetrahydrofuran (85 mL), and the reaction is stirred for 30 minutes at room temperature. Then ethyl bromoacetate (5.40 mL, 48.8 mmol) is added, and the reaction is stirred overnight at room temperature. The reaction is quenched with a small amount of water, and all the solvent is removed. The crude mixture is partitioned between ethyl acetate and water, the aqueous phase is extracted several times with ethyl acetate, the combined organic layers are dried (Na2SO4), and the solvent is evaporated. The product is purified by silica gel chromatography (30% ethyl acetate/hexane) to give ethyl 2-[[4-methoxybenzenesulfonyl](benzyl)amino]acetate.
Reaction SMILES: Cl.[N:2]1([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][N:4]=[N:3]1.C1CCN2C(=NCCC2)CC1.[NH2:24][C:25]1[C:34]([F:35])=[C:33](F)[C:32]([F:37])=[C:31]2[C:26]=1[C:27](=[O:44])[C:28]([C:41]([OH:43])=[O:42])=[CH:29][N:30]2[CH:38]1[CH2:40][CH2:39]1>C(#N)C>[NH2:24][C:25]1[C:34]([F:35])=[C:33]([N:9]2[CH2:10][CH2:11][CH2:12][CH:7]([N:2]3[CH:6]=[CH:5][N:4]=[N:3]3)[CH2:8]2)[C:32]([F:37])=[C:31]2[C:26]=1[C:27](=[O:44])[C:28]([C:41]([OH:43])=[O:42])=[CH:29][N:30]2[CH:38]1[CH2:40][CH2:39]1
Reactant: c1cncc(-n2ccnn2)c1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1c(F)c(N2CCCC(n3ccnn3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 38.7 %

Procedure:
3-(1,2,3-triazol-1-yl)pyridine hydrochloride (63 mg, 0.33 mmol) and DBU (77 mg, 0.5 mmol) were added to a suspension of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (50 mg, 0.18 mmol) in acetonitrile (5 ml). The reaction mixture was refluxed for 48 hrs and then concentrated under vacuo. The residue was diluted with water and thus separated solid was filtered, washed with water, acetonitrile and dried to give 30 mg of desired product. m.p. 252-254° C.; 1H NMR (TFA) δ: 9.36 (s, 1H), 8.65 (s, 1H), 8.53 (s, 1H), 5.28 (m, 1H), 3.60-4.66 (m, 5H), 2.10-2.58 (m, 4H), 1.32-1.68 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:11])=[C:4]([C:7]([O:9]C)=[O:8])[S:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([NH2:22])=[O:21]>CN(C=O)C>[NH2:22][C:20](=[O:21])[CH2:19][O:11][C:3]1[C:2]([Br:1])=[CH:6][S:5][C:4]=1[C:7]([OH:9])=[O:8]
Reactant: NC(=O)CBr
Reactant: COC(=O)c1scc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)COc1c(Br)csc1C(=O)O
Temperature: 85 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
A solution of methyl 4-bromo-3-hydroxythiophene-2-carboxylate (53.0 g), potassium carbonate (46.2 g), 2-bromoacetamide (37.0 g) and DMF (500 ml) was stirred at 60° C. for 2 hr, and the solvent was evaporated under reduced pressure. Water (300 ml) was added to the residue, and the solid was collected by filtration. To the obtained solid were added potassium carbonate (61.6 g), water (20 ml) and MeOH (500 ml, and the mixture was stirred at 85° C. for 1 hr. After cooling to room temperature, the solid were collected by filtration. The obtained solid was dissolved in water (300 mL), and the mixture was adjusted with 6 N hydrochloric acid to pH 3. The obtained solid was collected by filtration, and washed with water to give the title compound (50.5 g, 80.8%) as a solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:10]([CH3:16])=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])O1.[Br:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22](I)=[CH:21][C:20]=1[CH3:27]>>[Br:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([C:9]2[C:10]([CH3:16])=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])=[CH:21][C:20]=1[CH3:27]
Reactant: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1cc(I)cc(C)c1Br
Product: Cc1cc(-c2c(C)nn(C)c2C)cc(C)c1Br

Procedure:
The title compound is prepared from 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3,5-trimethyl-pyrazole and 2-bromo-5-iodo-1,3-dimethyl-benzene following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 7): tR=1.09 min; Mass spectrum (ESI+): m/z=293/295 (Br) [M+H]+.