Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=O)=[O:7])(C)(C)C.[CH:21](=O)C1C=CC=CC=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1>>[CH2:14]([CH:10]1[CH2:9][NH:8][C:6](=[O:7])[CH2:21][N:39]([S:36]([C:33]2[CH:32]=[CH:31][C:30]([Cl:29])=[CH:35][CH:34]=2)(=[O:37])=[O:38])[C:11]1=[O:13])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(Cc1ccccc1)C(=O)O
Product: O=C1CN(S(=O)(=O)c2ccc(Cl)cc2)C(=O)C(Cc2ccccc2)CN1

Procedure:
N-(tert-butoxycarbonyl)-2-benzyl-β-alanine synthesized by using benzaldehyde as the starting material for the similar procedure as in Reference Examples 2 to 5, Reference Example 23, and Reference Example 33 was used instead of the starting material of Reference Example 148, that is, the compound S33, and 4-chlorobenzenesulfonamide was used instead of 4-nitrobenzenesulfonamide for the similar procedure as in Reference Example 148 to Reference Example 150 and Example 173 to obtain the title compound.
Reaction SMILES: [Na].[CH2:2]([N:4]1[C:8]2=[N:9][C:10]([CH3:16])=[C:11]([C:13]([OH:15])=[O:14])[N:12]=[C:7]2[CH:6]=[N:5]1)[CH3:3].Cl[CH2:18][C:19]#[N:20]>CN(C)C=O>[CH2:2]([N:4]1[C:8]2=[N:9][C:10]([CH3:16])=[C:11]([C:13]([O:15][CH2:18][C:19]#[N:20])=[O:14])[N:12]=[C:7]2[CH:6]=[N:5]1)[CH3:3]
Reactant: CCn1ncc2nc(C(=O)O)c(C)nc21
Reactant: N#CCCl
Agent: [Na]
Solvent: CN(C)C=O
Product: CCn1ncc2nc(C(=O)OCC#N)c(C)nc21

Procedure:
9.12 g. of the sodium salt of 1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyrazine-5-carboxylic acid (0.04 mol.), 3.33 g. of chloroacetonitrile (0.056 mol.) and 90 ml. of dimethyl-formamide are stirred at 70°-80° for 12 hours. After vacuum removal of the dimethylformamide, the residue is stirred with 200 ml. of ether and filtered. The ethereal filtrate is evaporated and the residual 1-ethyl-6-methyl-1H-pyrazolo[3,4-b]-pyrazine-5-carboxylic acid, cyanomethyl ester is recrystallized from hexane, yield 3.76 g. (38%), m.p. 83°-84°. A polymorphous form melts at 111°-112°.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:15]=1[O:16][C:17]1[CH:28]=[CH:27][C:20]([C:21]([NH:23][CH2:24][CH2:25][CH3:26])=[O:22])=[CH:19][CH:18]=1>>[Cl:33][C:31]1[CH:30]=[CH:29][C:15]([O:16][C:17]2[CH:28]=[CH:27][C:20]([C:21]([NH:23][CH2:24][CH2:25][CH3:26])=[O:22])=[CH:19][CH:18]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:32]=1
Reactant: CCCNC(=O)c1ccc(Oc2ccc(Cl)cc2N)cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: CCCNC(=O)c1ccc(Oc2ccc(Cl)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (111 mg, 0.62 mmol) was reacted with the product from Example 127b (190 mg, 0.62 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (45.9 mg, 13%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.86 (t, J=7.54 Hz, 3 H) 1.39-1.60 (m, 2 H) 2.72 (s, 3 H) 3.08-3.26 (m, 2 H) 6.72 (d, J=6.99 Hz, 1 H) 6.96 (d, J=8.82 Hz, 2H) 7.29 (d, J=8.82 Hz, 1 H) 7.61 (dd, J=8.82, 2.57 Hz, 1 H) 7.69-7.80 (m, 4 H) 8.34 (t, J=5.52 Hz, 1H) 8.53 (d, J=6.99 Hz, 1 H) 8.82 (d, J=8.46 Hz, 1 H) 10.91 (s, 1 H) 14.55 (s, 1H); MS (ESI+) m/z 447 (M+H−TFA)+.
Reaction SMILES: B(Br)(Br)Br.[NH2:5][C:6]1[CH:14]=[C:13]([O:15]C)[C:12]([O:17]C)=[CH:11][C:7]=1[C:8]([NH2:10])=[O:9].O.[Cl:20]CCl>>[ClH:20].[NH2:5][C:6]1[CH:14]=[C:13]([OH:15])[C:12]([OH:17])=[CH:11][C:7]=1[C:8]([NH2:10])=[O:9]
Reactant: ClCCl
Reactant: COc1cc(N)c(C(N)=O)cc1OC
Agent: BrB(Br)Br
Solvent: O
Product: Cl
Product: NC(=O)c1cc(O)c(O)cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 76.6 g (306 mmol) of boron tribromide in 500 ml of dichloromethane was added dropwise at -78° C. a solution of 20 g (102 mmol) of 2-amino-4,5-dimethoxybenzamide in 1300 ml of dichloromethane. The mixture was allowed to warm slowly to room temperature with stirring overnight. Under ice cooling 250 ml of water added dropwise to the solution. The resulting precipitate was filtered off, washed with water and dried in vacuo over phosphorous pentoxide; yield of 2-amino-4-dihydroxybenzamide, monohydrochloride (contains boric acid) was 30.5 g. In order to remove the boric acid, crude 2-amino-4,5-dihydroxybenzamide, monohydrochloride (30.0 g) was suspended in 900 ml of absolute acetonitrile. Under ice cooling, 183 g bis(trimethylsilyl)acetamide were added, and the mixture was stirred for 1 hour to obtain a clear solution. The solvent was distilled off in high vacuum and the residual green oil was dissolved in 750 ml of absolute ether. After the addition of 165 ml of absolute methanol, an oil separated. The solvent was removed in vacuo and the residue evaporated in high vacuum for 45 minutes. 105 ml of water was added to the residue, and the pH was adjusted to 1 with 1N hydrochloric acid. After extraction with ether, the aqueous solution was freeze dried to yield 60.8 g of crude 2-amino-4,5-dihydroxybenzamide, monohydrochloride which contained acetamide as by-product. Crude 2-amino-4,5-dihydroxybenzamide, monohydrochloride was dissolved in 450 ml of ethanol and after the addition of 1450 ml of ether, 2-amino-4,5-dihydroxybenzamide, monohydrochloride crystallized out. After two days, the crystals were collected by filtration, washed with ether and dried in vacuo; yield: 11.3 g, melting point >300° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][N:12]2[CH2:17][CH:16]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:14][CH2:13]2)=[CH:2]1.[CH3:27][CH2:28][CH2:29]CCC.C(Br)C=C>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][N:12]2[CH2:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH2:29][CH:28]=[CH2:27])[CH:19]=3)[CH2:16][CH2:17]2)=[CH:2]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCN(CCc2csc3ccccc23)C1
Reactant: CCCCCC
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCn1cc(C2=CCN(CCc3csc4ccccc34)CC2)c2ccccc21
Reaction time: 5.5 h

Procedure:
3-{1-[2-(1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole (358 mg, 1 mmol) (obtained from example 29, step 2) in dry THF (50 ml) was slowly added to a stirred suspension of hexane and washed with 60% sodium hydride (44 mg) at 0° C. After the addition, the reaction mixture was stirred for 330 min and allyl bromide (183 mg, 1.5 mmol) was added. The reaction mixture was stirred for 4 hrs and quenched carefully with ice cold water. The reaction mixture was extracted with chloroform; washed well with water; dried over anhydrous MgSO4; filtered and concentrated. The residue obtained was purified by silica-gel column chromatography by eluting it with 50% ethyl acetate:hexane. Yellow semi-solid. Yield: 195 mg (48%); 399 (M+H); 1HNMR (400 MHz, CDCl3): δ 7.99˜7.87 (m, 3H); 7.42˜6.99 (m, 6H); 6.22˜6.21 (s, 1H); 5.22˜5.21 (d, J=1.3 Hz, 2H); 5.20˜5.19 (d, J=1.3 Hz, 2H); 4.71˜4.65 (d, 1.6 Hz, 2H); 3.49˜2.67 (m, 10H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([OH:21])=O)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2].Cl.[CH2:30]([C:32]1[N:36]=[C:35]([CH2:37][N:38]2[C:43]3[CH:44]=[C:45]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[S:46][C:42]=3[C:41](=[O:53])[N:40]([CH:54]3[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]3)[C:39]2=[O:60])[O:34][N:33]=1)[CH3:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:17]=[C:18]([C:19]([N:57]4[CH2:58][CH2:59][CH:54]([N:40]5[C:41](=[O:53])[C:42]6[S:46][C:45]([C:47]7[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=7)=[CH:44][C:43]=6[N:38]([CH2:37][C:35]6[O:34][N:33]=[C:32]([CH2:30][CH3:31])[N:36]=6)[C:39]5=[O:60])[CH2:55][CH2:56]4)=[O:21])[CH:22]=[CH:23][CH:24]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Reactant: CCOc1cc2c(cc1OC)C(c1cccc(C(=O)O)c1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1cccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5nc(CC)no5)c4=O)CC3)c1)=N[C@@H]1CCSC[C@H]21

Procedure:
The title compound is prepared analogously as described for example 1 using 3-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (159 mg; compound C8), 1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-6-phenyl-3-piperidin-4-ylthieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (190 mg; compound B32), HBTU (167 mg), DIPEA (0.28 ml) and DCM (3 ml). The crude product is purified by flash column chromatography (amino phase silica gel, eluent gradient: EtOAc/methanol, 98/2 to 95/5 (v/v)) and afterwards by preparative TLC [silica gel, eluent: EtOAc/MeOH/triethylamine, 92.5/5/2.5 (v/v/v)] to yield the title compound as a solid.
Reaction SMILES: CC(=NC1C=CC=CC=1)C(=NC1C=CC=CC=1)C.[H][H].[OH:21][N:22]1[C:27]([CH3:29])([CH3:28])[CH2:26][C:25](=[O:30])[CH2:24][C:23]1([CH3:32])[CH3:31].OO.N=O.[C:37]([OH:41])([CH3:40])([CH3:39])[CH3:38]>>[OH:41][C:37]([CH3:40])([CH3:39])[CH2:38][O:21][N:22]1[C:27]([CH3:28])([CH3:29])[CH2:26][C:25](=[O:30])[CH2:24][C:23]1([CH3:32])[CH3:31]
Reactant: CC1(C)CC(=O)CC(C)(C)N1O
Reactant: CC(C)(C)O
Reactant: [H][H]
Agent: CC(=Nc1ccccc1)C(C)=Nc1ccccc1
Agent: N=O
Agent: OO
Product: CC(C)(O)CON1C(C)(C)CC(=O)CC1(C)C
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a mixture of 0.994 g (5 mmol) of ferrous chloride tetrahydrate and 150 mL of tert-butyl alcohol at 35° C. are added, sequentially, 1.18 g (5.0 mmol) of N,N'-(1,2-dimethyl1,2-ethanediylidene)bis(benzenamine), where in formula IV, X is hydrogen, and 17.0 g (100 mmol) of 1-oxyl-2,2,6,6-tetramethylpiperidin-4-one. A solution of 47.5 g (700 mmol) of 50% aqueous hydrogen peroxide mixed with 60 mL of tert-butyl alcohol is added over eight hours at 35-40° C. to the above mixture. The reaction is stirred an additional 16 hours at 40° C. Analysis by gas chromatography shows less than 4% starting nitroxyl present. Solids are removed by filtration, and the filtrate is reacted with aqueous sodium sulfite to decompose excess peroxide. The reaction mixture is thoroughly extracted with ethyl acetate to afford, after concentration, 21.4 g of crude product containing greater than 93% of the title compound as based on gas chromatography.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[I-:12].[K+].ClCCl.C(OCC)C>CN(C)C=O.[Cu]I>[I:12][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2
Reactant: [I-]
Reactant: Brc1ccc2cnccc2c1
Agent: [Cu]I
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: ClCCl
Product: Ic1ccc2cnccc2c1
Yield: 101.8 %

Procedure:
Heat a mixture of 6-bromoisoquinoline (Aldrich; 0.320 g, 1.54 mmol), copper (I) iodide (0.155 g, 0.815 mmol), and potassium iodide (1.27 g, 7.96 mmol) in N,N-dimethylformamide (5.0 mL) to 130° C. at 3 h under microwave irradiation. Pour the cooled reaction mixture into 4:1 dichloromethane/diethyl ether (100 mL) and filter. Wash the filtrate with 5% aqueous sodium bisulfite solution (2×50 mL). Dry the organic layer over sodium chloride, decant the organic layer, and remove the solvents under reduced pressure. Dry the residue under vacuum for 18 h to give 0.4 g (100%) of the title compound as a dark red-brown solid. This material is carried on directly to the next step without further purification. MS (electrospray, m/z) 256.1 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[Cl:15])[N:5]=[C:4]([NH2:16])[N:3]=1.[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.C(OCC)(=O)C>C(O)C>[Br:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=3[Cl:15])[N:5]=[C:4]([NH2:16])[N:3]=2)=[CH:20][CH:19]=1
Reactant: Nc1ccc(Br)cc1
Reactant: Nc1nc(Cl)cc(-c2cc(Cl)ccc2Cl)n1
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1nc(Nc2ccc(Br)cc2)cc(-c2cc(Cl)ccc2Cl)n1
Reaction time: 0.5 h
Yield: 59 %

Procedure:
A mixture of the hydrochloride salt of 4-chloro-6-(2,5-dichloro-phenyl)-pyrimidin-2-yl-amine (0.03 g, 0.096 mmol) and 4-bromoaniline (0.034 g, 0.020 mmol) in ethanol (7.5 ml) was heated under reflux for 1 hour. After evaporation of the solvent under reduced pressure, the residue was treated with 1.0 N hydrochloric acid (10 ml) and stirred for 30 minutes. Filtration provided the crude product, which was treated with ethyl acetate (10 ml) and stirred for 1 hour. After filtration the solid was dissolved in methanol (10 ml) and treated with aqueous sodium carbonate solution (1.0 M, 1 ml). After stirring for 1 hour, the solvent was evaporated under reduced pressure and the solid was treated with water (10 ml). After stirring for 15 minutes, filtration provided the title compound (59% yield) as a white powder. 1H NMR (DMSO-d6) δ 6.31 (s, 1H, Ar), 6.54 (s, 2H, NH2), 7.45 (d, 2H, J=8.9 Hz, Ar), 7.52 (dd, 1H, J=8.6 Hz, J-2.6 Hz, Ar), 7.60 (d, 1H, J=8.6 Hz, Ar), 7.64 (d, 1H, J=2.6 Hz, Ar), 7.77 (d, 2H, J=8.9 Hz, Ar), 9.46 (s, 1H, NH).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16](OC)=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH2:46][C:47]1[C:55]2[C:50](=[CH:51][C:52]([F:56])=[CH:53][CH:54]=2)[N:49]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[N:48]=1.O>CN(C=O)C.C1(C)C=CC=CC=1>[F:56][C:52]1[CH:51]=[C:50]2[C:55]([C:47]([CH2:46][CH:3]3[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[O:11])[C:7]4[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=4[N:5]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:4]3=[O:34])=[N:48][N:49]2[C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])=[CH:54][CH:53]=1
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccc(F)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N(C(=O)CN1C(=O)C(Cc2nn(C(=O)OC(C)(C)C)c3cc(F)ccc23)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a solution of 427 mg of 2-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide in 5 mL of dry DMF at 0° C. is added 2.2 mL of a 0.5M solution of potassium bis(trimethylsilyl)amide in toluene. The reaction mixture is stirred for 30 min at 0° C. and a solution of 329 mg of 3-Bromomethyl-6-fluoro-1-tert-butoxycarbonyl indazole in 2 mL of dry DMF is added dropwise. The reaction mixture is stirred overnight at RT, poured into water and the product extracted with ethyl acetate (2×15 mL). The solvent is removed in vacuo and the residue is purified by silica gel flash column chromatography (MeOH 1%:CHCl3 99%) to afford 410 mg of the title compound: 1H NMR (400 MHz, CDCl3) δ7.85-6.91 (m, 17H), 5.01 (m, 1H,J=6.8), 4.22 (m, 3H), 3.81 (dd, 1H, J=16.5, 8.9), 3.51 (dd, 1H, J=16.5, 4.7), 1.68 (s, 9H), 1.07 (d, 6H, J=6.8).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([CH:15]=2)[NH2:14])[CH2:3]1.CN1CCOCC1.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[C:28]([CH3:36])[CH:27]=1>ClCCl>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:14][C:13]2[CH:15]=[C:9]([N:4]3[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]3)[CH:10]=[CH:11][C:12]=2[O:16][CH3:17])(=[O:34])=[O:33])=[C:28]([CH3:36])[CH:27]=1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1N
Reactant: Cc1cc(Br)ccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)aniline (D4) (1.20 g, 5.1 mmol) in dichloromethane (35 ml) was treated with morpholinomethyl-polystyrene HL resin (2.43 g, 4.2 mmol/g loading, 10.2 mmol) followed by 4-bromo-2-methylbenzenesulfonyl chloride (2.75 g, 10.2 mmol). The resulting solution was stirred at room temperature overnight, the resin filtered off, the solvent evaporated in vacuo and the residue passed through an SCX column eluting first with methanol and then 2M ammonia in methanol. The basic fractions were combined and solvent evaporated in vacuo to afford a crude product which was purified further by chromatography on silica gel using a Flashmaster and an elution gradient of 0 to 10% methanol in dichloromethane. The relevant fractions were combined and the solvent evaporated in vacuo to afford the title compound (E102). MS (ES+) m/e 468/470 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH2:11][OH:12])=[N:10][C:5]2=[N:4][CH:3]=1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>ClCCl>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH2:11][O:12][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccn2c(Br)cnc2n1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1ccn2c(Br)cnc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
3-Bromoimidazo[1,2-α]pyrimidin-7-ylmethanol (912 mg, 4.00 mmol) was dissolved in dichloromethane (10 ml) and treated with imidazole (0.70 g, 10.3 mmol) and tert-butyldimethylsilyl chloride (0.77 g, 5.1 mmol) and the mixture left to stir at ambient temperature for 1 h. The reaction was diluted with dichloromethane (75 ml) and washed with 0.01N hydrochloric acid (2×50 ml). The organic phase was washed with saturated sodium hydrogencarbonate solution (50 ml), water (50 ml) and brine (50 ml), dried over anhydrous magnesium sulfate, filtered and evaporated to give crude 3-bromo-7-(tert-butyldimethylsilanyloxymethyl)imidazo[1,2-α]pyrimidine (1.37 g, 100%) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.[CH:19]1[N:23]=[CH:22][N:21]([C:24](N2C=NC=C2)=O)[CH:20]=1.CN(C)CCN>>[CH3:22][N:21]([CH3:24])[CH2:20][CH2:19][NH:23][C:14]([C:7]1([CH3:17])[CH2:6][CH2:5][C:4]2[C:9](=[C:10]([CH3:13])[C:11]([CH3:12])=[C:2]([OH:1])[C:3]=2[CH3:18])[O:8]1)=[O:16]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)CCN
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCN(C)C)O2
Yield: 75.9 %

Procedure:
Following the amide coupling procedure described in protocol A, 1.03 g 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (4.11 mmol), 0.712 g CDI (4.39 mmol) and 704 mg N,N-dimethylethylenediamine (7.99 mmol) produced 1 g of N-(2-(dimethylamino)ethyl)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide as a white crystalline solid.
Reaction SMILES: [C:1]1([C@@H:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)([O-:31])=[O:30].COCCOC(N=NC(OCCOC)=O)=O>C1COCC1.O>[N+:29]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([O:9][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])=[O:37])=[CH:39][CH:40]=1)([O-:31])=[O:30].[C:1]1([C@@H:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: C[C@H](O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](OC(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1
Reaction time: 4 h

Procedure:
After (S)-1-phenylethyl alcohol (300 mg, 2.46 mmol), triphenylphosphine (771 mg, 2.95 mmol), 4-nitrobenzoic acid (494 mg, 2.95 mmol), and THF (12 ml) were added to a 50 ml flask, azodicarboxylic acid bis(2-methoxyethyl) ester (691 mg, 2.95 mmol) dissolved in THF (6 ml) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for four hours. Water (0.5 mL) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was carried out using diethyl ether (10 ml, ×2). Then, the organic layer was washed with water (10 mL) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 5% ethyl acetate-hexane solution) to give (R)-1-(4-nitrobenzoyloxy)-1-phenylethane as a pale yellow liquid substance (559 mg, yield: 84%/(S)-1-phenylethyl alcohol).
Reaction SMILES: [S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([CH:20]=[N:21][N:22]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl[C:57]1[C:58](=[O:69])[C:59](C#N)=[C:60]([C:65]#N)[C:61](=O)[C:62]=1Cl>C(Cl)Cl.O>[CH2:61]([CH:60]1[CH:65]([C:20]2[N:19]3[C:14]4[CH:13]=[CH:12][N:11]([S:1]([C:4]5[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=5)(=[O:2])=[O:3])[C:15]=4[N:16]=[CH:17][C:18]3=[N:22][N:21]=2)[CH2:57][CH:58]([OH:69])[CH2:59]1)[CH3:62]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nncn23)cc1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CCC1CC(O)CC1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
To 2-ethyl-4-(4-methoxybenzyloxy)cyclopentyl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (1.153 g, 2.11 mmol, prepared using Z from Preparation #EE.1, A from Example #1, Step D, HATU, and TEA, B with DIEA) in DCM (18 mL) and water (3.5 mL) was added 2,3-dichloro-5,6-dicyano-p-benzoquinone (0.576 g, 2.54 mmol). The reaction mixture was stirred at ambient temperature for about 16 h. The solid was removed by filtration while washing with DCM (150 mL). The organic layer was separated and washed with saturated aqueous NaHCO3 (2×40 mL) and brine (40 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The residue was purified using silica gel chromatography (40 g) eluting with a gradient of 30-100% EtOAc in DCM to give 3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol (0.672 g, 75%): LC/MS (Table 1, Method b) Rt=2.09 min; MS m/z: 426 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[C:10]([O:27][CH3:28])=[CH:11][C:12]([Br:26])=[C:13]2[C:18]=1[CH2:17][N:16]([NH:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)[CH2:15][CH2:14]2)C1C=CC=CC=1>C(O)C.[Pd]>[BrH:26].[CH3:28][O:27][C:10]1[C:9]([OH:8])=[C:18]2[C:13]([CH2:14][CH2:15][N:16]([NH:19][C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)[CH2:17]2)=[CH:12][CH:11]=1
Reactant: COc1cc(Br)c2c(c1OCc1ccccc1)CN(Nc1ccncc1)CC2
Agent: [Pd]
Solvent: CCO
Product: Br
Product: COc1ccc2c(c1O)CN(Nc1ccncc1)CC2
Yield: 94.6 %

Procedure:
(8-Benzyloxy-5-bromo-3,4-dihydro-7-methoxy-1H-isoquinolin-2-yl)-4-pyridinylamine) (11 g) was dissolved in ethanol (250 ml) and slowly added to 5% palladium-on-carbon (2.2 g). The mixture was hydrogenated at 55 psi overnight in a parr shaker at ambient temperature. The reaction mixture was filtered through a pad of Celite, and the pad was washed well with methanol. The filtrate was concentrated, and the precipitate was collected and dried to give 8.3 g, 94.6% of product, mp 235-236° C.