Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[CH2:11][CH:10]2[C:6]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)([NH:7][O:8][CH2:9]2)[CH2:5]1)C=C>C(Cl)(Cl)Cl.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:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:6]23[CH2:5][NH:4][CH2:11][CH:10]2[CH2:9][O:8][NH:7]3)[CH:13]=1
Reactant: C=CCN1CC2CONC2(c2cccnc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: c1cncc(C23CNCC2CON3)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
5-Allyl-6a-(3-pyridyl)-3,3a,4,6-tetrahydro-1H-pyrrolo[3,4-c]isoxazole (2.14 g, 7.40 mmol) and N,N-dimethylbarbituric acid (6.93 g, 44.41 mmol) are dissolved in chloroform (80 mL) and the resulting solution is degassed twice using liquid nitrogen. Tetrakis(triphenylphosphine)palladium (1.28 g, 1.11 mmol) is added and the mixture is stirred at room temperature for 2 hours. The reaction is concentrated under reduced pressure. The resulting residue is dissolved in a 1:1 mixture of dimethylsulfoxide/methanol (40 ml) and the solution is loaded on an ion exchange column. The material is eluted with methanol (70 mL) then with 7 M ammonia/methanol solution (70 mL). The basic fraction is collected and concentrated under reduced pressure. The product is further purified by silica gel column chromatography using a 0-15% gradient of 0.14 M ammonia/methanol solution in dichloromethane to give the title compound (1.28 g, 86%). ES/MS (m/e): 192 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]=[C:10]([C:13](=[N:15][NH:16][C:17]([N:19]3[CH2:24][CH2:23][CH:22]([C:25](O)=[O:26])[CH2:21][CH2:20]3)=[S:18])[CH3:14])[C:9]=2[OH:28])=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[N:60]1[CH:65]=[CH:64][C:63]([CH2:66][NH2:67])=[CH:62][CH:61]=1>O.CN(C)C=O>[N:60]1[CH:65]=[CH:64][C:63]([CH2:66][NH:67][C:25]([CH:22]2[CH2:21][CH2:20][N:19]([C:17]([NH:16][N:15]=[C:13]([C:10]3[C:9]([OH:28])=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=4)[S:12][CH:11]=3)[CH3:14])=[S:18])[CH2:24][CH2:23]2)=[O:26])=[CH:62][CH:61]=1
Reactant: NCc1ccncc1
Reactant: CC(=NNC(=S)N1CCC(C(=O)O)CC1)c1csc(-c2ccc(Br)cc2)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(=NNC(=S)N1CCC(C(=O)NCc2ccncc2)CC1)c1csc(-c2ccc(Br)cc2)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To 1-{1-[5-(4-bromophenyl)-4-hydroxythiophen-3-yl]-ethylidene-hydrazinothiocarbonyl}-piperidine-4-carboxylic acid (84 mg, 0.17 mmol) prepared in Synthetic Example 9, dimethylformamide (2 mL) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (66 mg, 0.25 mmol) and HOBt (47 mg, 0.25 mmol) were added, and then dimethylformamide (2.5 mL) and diisopropylethylamine (91 μl, 0.52 mmol) were added. The resulting solution was stirred at room temperature for 1 hour and then stirred with a dimethylformamide solution (1.5 mL) of 4-picolylamine (47 mg, 0.43 mmol) for 24 hours. After addition of water, the reaction mixture was filtered, and the filter cake was dried and washed with isopropyl alcohol repeatedly to give the desired product (yield 34%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:7].Br[C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[CH3:36][C:30]([O:23][C:20]1[CH:21]=[CH:22][C:17]([C:14]2[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:16][CH:15]=2)=[CH:18][CH:19]=1)([CH3:37])[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: COc1ccc(C(=O)NCCc2ccc(-c3ccc(O)cc3)cc2)cc1OC
Product: CCOC(=O)C(C)(C)Oc1ccc(-c2ccc(CCNC(=O)c3ccc(OC)c(OC)c3)cc2)cc1
Yield: 22 %

Procedure:
Ethyl 2-methyl-2-{4-[2-(3,4-dimethoxy-benzamido)-ethyl]-biphenyl-4'-oxy}-propionate was prepared from 4-[2-(3,4-dimethoxy-benzamido)-ethyl]-4'-hydroxy-biphenyl and ethyl 2-bromo-2-methyl-propionate analogous to Example 31. Yield: 22% of theory; m.p. 118° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:9][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[O:13][CH2:12][CH2:11][O:10]1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(c2ccc(Br)cc2)OCCO1

Procedure:
In 1200 milliliters of toluene in a flask equipped with a Dean-Stark tube are dissolved 100 grams of p-bromoacetophenone and to this solution is added 140 grams of ethylene glycol and 5 grams of p-toluenesulphonic acid. This mixture is refluxed until no further water collects in the Dean-Stark tube. After distilling off 600 milliliters of toluene, the remaining solution is decanted off and evaporated to dryness in vacuo to obtain 2-methyl-2-(p-bromophenyl)-1,3-dioxolane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[CH2:6][CH2:7][C:8]1[S:9][C:10]2[N:11]=[C:12]([NH2:23])[N:13]=[C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:15]=2[N:16]=1.[Br:27][C:28]1[CH:38]=[CH:37][C:31]([O:32][CH2:33][C:34](O)=[O:35])=[CH:30][CH:29]=1>>[NH2:23][C:12]1[N:13]=[C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:34](=[O:35])[CH2:33][O:32][C:31]3[CH:37]=[CH:38][C:28]([Br:27])=[CH:29][CH:30]=3)[CH2:19][CH2:18]2)[C:15]2[N:16]=[C:8]([CH2:7][CH2:6][C:5]3[CH:24]=[CH:25][CH:26]=[C:3]([O:2][CH3:1])[CH:4]=3)[S:9][C:10]=2[N:11]=1
Reactant: COc1cccc(CCc2nc3c(N4CCNCC4)nc(N)nc3s2)c1
Reactant: O=C(O)COc1ccc(Br)cc1
Product: COc1cccc(CCc2nc3c(N4CCN(C(=O)COc5ccc(Br)cc5)CC4)nc(N)nc3s2)c1
Yield: 65 %

Procedure:
This compound was prepared from 2-(3-methoxyphenethyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-bromophenoxyacetic acid in a yield of 65%, according to the procedure for the synthesis of example 50.
Reaction SMILES: [ClH:1].[CH2:2]([NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].S(Cl)([Cl:30])=O>>[ClH:30].[CH2:2]([NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([Cl:1])=[O:24])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Agent: Cl
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Reaction time: 20 h

Procedure:
A mixture of 1.00 g of 4-(n-hexadecylamino)benzoic acid hydrochloride and 5.00 ml of thionyl chloride is allowed to stand at ambient temperature for 20 hours and then is concentrated in vacuo to yield 4-(n-hexadecylamino)benzoyl chloride hydrochloride as an orange solid.
Reaction SMILES: O1CCCC1.C([NH:13][C:14]1[C:15]([CH3:27])=[C:16]([CH3:26])[C:17]2[O:21][C:20]([CH3:23])([CH3:22])[C:19](=[O:24])[C:18]=2[CH:25]=1)C1C=CC=CC=1>[C].[Pd].CO>[NH2:13][C:14]1[C:15]([CH3:27])=[C:16]([CH3:26])[C:17]2[O:21][C:20]([CH3:22])([CH3:23])[C:19](=[O:24])[C:18]=2[CH:25]=1
Reactant: Cc1c(NCc2ccccc2)cc2c(c1C)OC(C)(C)C2=O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(N)cc2c(c1C)OC(C)(C)C2=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 100 %

Procedure:
5% palladium carbon (50% water content, 9.50 g) was added to a mixed solution of tetrahydrofuran (100 mL) and methanol (100 mL) containing 5-(benzylamino)-2,2,6,7-tetramethyl-1-benzofuran-3(2H)-one (9.48 g, 32.1 mmol) synthesized in Reference Example 19, and the mixture was stirred under hydrogen atmosphere at room temperature for 22 hours. Palladium carbon was removed by filtration, and then the solvent was removed under reduced pressure to give 6.59 g of the title compound (yield: 100%).
Reaction SMILES: [NH:1]([C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])[C@H:2]([C:8]([NH:10][C@H:11]([C:29]([N:31]1[CH2:70][CH2:69][CH2:68][C@H:32]1[C:33]([NH:35][C@H:36]([C:38]([NH:40][C@H:41]([C:58]([O:60]CC1C=CC=CC=1)=[O:59])[CH2:42][CH2:43][CH2:44][CH2:45][NH:46][C:47]([O:49][CH2:50][C:51]1[CH:57]=[CH:56][CH:55]=[CH:54][C:52]=1[Cl:53])=[O:48])=[O:39])[CH3:37])=[O:34])=[O:30])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:28])[NH:17][S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[OH-].[Na+].C(Cl)(Cl)Cl.CO>CO>[NH:1]([C:71]([O:73][C:74]([CH3:75])([CH3:77])[CH3:76])=[O:72])[C@H:2]([C:8]([NH:10][C@H:11]([C:29]([N:31]1[CH2:70][CH2:69][CH2:68][C@H:32]1[C:33]([NH:35][C@H:36]([C:38]([NH:40][C@H:41]([C:58]([OH:60])=[O:59])[CH2:42][CH2:43][CH2:44][CH2:45][NH:46][C:47]([O:49][CH2:50][C:51]1[CH:57]=[CH:56][CH:55]=[CH:54][C:52]=1[Cl:53])=[O:48])=[O:39])[CH3:37])=[O:34])=[O:30])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:28])[NH:17][S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
At 0° C. to the solution of 770 mg (0.694 mmol) of Boc-Gln-Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 16) in 18 ml of methanol 5 ml of the solution of NaOH in methanol (2 mol/L) were added. The reaction mixture was stirred at 0° C. for 2 h and TLC (chloroform/methanol, 15:1) indicated complete disappearance of Boc-Gln-Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 16). The reaction mixture was neutralized to pH 7 and evaporated at room temperature to remove methanol. The residue was acidified to pH 1–2 with hydrochloric acid (2 mol/L) to provide 610 mg (86%) of the title compound as a colorless powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:13])[CH2:11]Cl.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)C(C)C)(C)C>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:13])[CH2:11][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: Cc1cccc(C)c1NC(=O)CCl
Reactant: C1CNCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1cccc(C)c1NC(=O)CN1CCNCC1

Procedure:
To a solution of compound 3 (5 g, 25.2 mmol) in ethanol (100 mL) was added piperazine 4 (2.1 g, 25.0 mmol) and N,N-diisopropylethylamine (3.2 g, 25.2 mmol). The reaction mixture was refluxed for 24 h. The mixture was concentrated in vacuo and the residue was purified by column chromatography (10:1 DCM: MeOH) to afford compound 5.
Reaction SMILES: CN(C)C=[N:4][S:5]([C:8]1[O:16][C:15]2[CH:14]=[C:13]([CH3:17])[N+:12]([O-])=[CH:11][C:10]=2[CH:9]=1)(=[O:7])=[O:6].Cl.C(=O)([O-])[O-:22].[Na+].[Na+].C(OCC)C>C(OC(=O)C)(=O)C>[S:5]([C:8]1[O:16][C:15]2[CH:14]=[C:13]([CH2:17][OH:22])[N:12]=[CH:11][C:10]=2[CH:9]=1)(=[O:7])(=[O:6])[NH2:4]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc2oc(S(=O)(=O)N=CN(C)C)cc2c[n+]1[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: NS(=O)(=O)c1cc2cnc(CO)cc2o1
Temperature: 140 °C
Yield: 43 %

Procedure:
A mixture of N,N-dimethyl-N'-(5-oxido-6-methylfuro[3,2-c]pyridine-2-sulfonyl)formamidine (3.96 g, 14 mmol) in acetic anhydride (12 ml), under a nitrogen atmosphere was heated at 140° C. for 15 minutes to give a dark brown solution. The reaction was cooled to 100° C. and 20% aqueous hydrochloric acid (40 ml) was added and heat was maintained at this temperature for 4 hours. The cooled reaction was carefully made basic with sodium carbonate solution and then exhaustively extracted with ethyl acetate/methanol to isolate product. This extract was dried over sodium sulfate, filtered through a charcoal pad and solvent evaporated to give, after trituration of the residue with diethyl ether, nearly pure product (1.39 g, 43% yield). Recrystallization from hot ethanol afforded pure product (1.14 g), mp 222°-223° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:16][CH:17]=[CH:18][C:19]=3[NH:20][S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=O.[CH3:27][NH2:28].C1COCC1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH3:27][NH:28][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:16][CH:17]=[CH:18][C:19]=3[NH:20][S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(-c2ccc(C=O)cc2)cc1
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CNCc1ccc(-c2ccc(-c3sccc3NS(=O)(=O)C(C)C)cc2)cc1
Reaction time: 0.08 h

Procedure:
Mix propane-2-sulfonic acid [2-(4′-formyl-biphenyl-4-yl)-thiophen-3-yl]-amide (0.16 mmol) in 1,2-dichloroethane (2 ml) and add methylamine 2N in THF (0.16 ml, 0.32 mmol) at room temperature. Stir the resulting solution for 5 min before adding Na(OAc)3BH (0.32 mmol). Stir the mixture at room temperature for 16 h. Analyze by LC/MS for final product. Add saturated NaHCO3 aqueous solution and dichloromethane and filter the mixture through hydrophobic filter. Evaporate the filtrate and apply the residue to SCX cartridge, elute with MeOH/DCM to remove non-basic materials, followed by 2N NH3 in MeOH to give a crude product. Purify by flash chromatography (Silica gel-Dichloromethane/Methanol 7:1)to yield the title compound. MS (ES−): 399(M−1).
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[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.Cl.[O:24]1[CH2:29][CH2:28][CH2:27][CH:26]([NH2:30])[CH2:25]1.CCN(C(C)C)C(C)C>>[CH3:22][C:3]1[C:2]([NH:30][CH:26]2[CH2:27][CH2:28][CH2:29][O:24][CH2:25]2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: NC1CCCOC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1CCCOC1
Temperature: 100 °C
Yield: 75 %

Procedure:
Prepared similarly to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 44 mg, 0.148 mmol), rac-tetrahydro-2H-pyran-3-amine hydrochloride (40.9 mg, 0.297 mmol, Matrix Scientific, Columbia, S.C.), and DIPEA (129 μl, 0.742 mmol), heating at 100° C. for 1 h. Purification by silica gel (100% DCM to 6% MeOH/DCM) provided rac-2-(2-methyl-3-((tetrahydro-2H-pyran-3-yl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (75% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.72-1.83 (m, 3H) 2.13-2.21 (m, 1H) 2.56 (s, 3H) 2.91 (t, J=6.85 Hz, 2H) 3.35-3.42 (m, 2H) 3.45 (td, J=6.85, 2.35 Hz, 2H) 3.87 (d, J=10.76 Hz, 1H) 4.01-4.08 (m, 1H) 4.12-4.20 (m, 1H) 6.86 (d, J=7.24 Hz, 1H) 6.94 (br. s., 1H) 7.08 (d, J=2.15 Hz, 1H) 7.35 (t, J=7.82 Hz, 1H) 7.59 (dd, J=8.12, 1.27 Hz, 1H) 7.91 (dd, J=7.53, 1.27 Hz, 1H) 12.07 (br. s., 1H). MS (ESI, pos. ion) m/z: 378.2 (M+1). Chiral purification [SFC: Chiralpak OH-J (30×150 mm), A: liquid CO2, B: 20 mM NH3 in MeOH/EtOH/isopropanol (1:1:1), isocratic: 70:30 (A:B), 70 mL/min] separately afforded 2-(2-methyl-3-((tetrahydro-2H-pyran-3-yl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (first eluting enantiomer, 208) and 2-(2-methyl-3-((tetrahydro-2H-pyran-3-yl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (second eluting enantiomer, 209).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:30])=[CH:5][C@@H:6]1[N:20]2[C:21]([C@H:23]3[N:27]([C:28](=[O:29])[C@@H:19]2[CH2:18][C:8]2[C:9]4[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[CH:13][C:14]=4[NH:15][C:7]1=2)[CH2:26][CH2:25][CH2:24]3)=[O:22].[CH3:31][C:32]([CH3:36])=[CH:33][CH2:34]Br.[Cl-].[NH4+]>ClCCl>[CH3:17][O:16][C:12]1[CH:13]=[C:14]2[C:9]([C:8]3[CH2:18][C@H:19]4[C:28](=[O:29])[N:27]5[CH2:26][CH2:25][CH2:24][C@H:23]5[C:21](=[O:22])[N:20]4[C@@H:6]([CH:5]=[C:4]([CH3:30])[CH3:3])[C:7]=3[N:15]2[CH2:34][CH:33]=[C:32]([CH3:36])[CH3:31])=[CH:10][CH:11]=1
Reactant: CC(C)=CCBr
Reactant: COc1ccc2c3c([nH]c2c1)[C@H](C=C(C)C)N1C(=O)[C@@H]2CCCN2C(=O)[C@@H]1C3
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: ClCCl
Product: COc1ccc2c3c(n(CC=C(C)C)c2c1)[C@H](C=C(C)C)N1C(=O)[C@@H]2CCCN2C(=O)[C@@H]1C3

Procedure:
To a stirred suspension of sodium hydride (0.12 mol) in dry dichloromethane (0.1 ml) was added a solution of fumitremorgin C (0.05 mmol) in dichloromethane (0.5 ml) under an atmosphere of nitrogen at room temperature. Upon stirring for forty-five minutes, 3,3-dimethyl allyl bromide (0.11 mmol) was added and the reaction mixture stirred under nitrogen for two hours. Saturated aqueous solution of ammonium chloride was then added, and the alkylation product was extracted with ethyl acetate and purified by HPLC on a C18 column using methanol/water as mobile phase. MS and 1H NMR spectra were consistent with the desired product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26](Br)[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:32]([O:36][C:37](=[O:49])[NH:38][CH2:39][CH2:40][CH:41]([NH2:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:35])([CH3:34])[CH3:33].CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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.[Pd].[Pd]>[C:1]([O:5][C:6](=[O:31])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:48][CH:41]([C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)[CH2:40][CH2:39][NH:38][C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:49])[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2nccn3c(-c4cccc(Br)n4)cnc23)CC1
Reactant: CC(C)(C)OC(=O)NCCC(N)c1ccccc1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCC(Nc1cccc(-c2cnc3c(NC4CCC(NC(=O)OC(C)(C)C)CC4)nccn23)n1)c1ccccc1
Temperature: 130 °C

Procedure:
A mixture of {4-[3-(6-bromo-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 40 supra) (0.487 g, 1.0 mmol), (3-amino-3-phenyl-propyl)-carbamic acid tert-butyl ester (from Example 53 supra) (0.375 g, 1.5 mmol), Pd2(dba)3 (60 mg), Davephos (80 mg), K2CO3 (207 mg, 1.5 mmol) in dioxane (25 mL) in a sealed tube was bubbled with N2 for several minutes and then heated under N2 at 130° C. for 15 hours. The solution was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified first by chromatography (CH2Cl2:MeOH, 100:1), then by preparative-HPLC to give (4-{3-[6-(3-tert-butoxycarbonylamino-1-phenyl-propylamino)-pyridin-2-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester. (Yield 250 mg). LC-MS: [M+H]+ 657.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:50]=[CH:49][C:12]([O:13][CH2:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:28]([OH:35])=[C:27]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:26]=4)=[CH:20][C:19]=3[N:40]([CH3:48])C(=O)OC(C)(C)C)=O)=[CH:11][CH:10]=2)[S:3]1.[ClH:51].O1CCOCC1>>[ClH:51].[C:36]([C:27]1[CH:26]=[C:25]([CH:30]=[C:29]([C:31]([CH3:32])([CH3:34])[CH3:33])[C:28]=1[OH:35])[O:24][C:21]1[CH:22]=[CH:23][C:18]2[N:17]=[C:15]([CH2:14][O:13][C:12]3[CH:11]=[CH:10][C:9]([CH2:8][CH:4]4[S:3][C:2](=[O:1])[NH:6][C:5]4=[O:7])=[CH:50][CH:49]=3)[N:40]([CH3:48])[C:19]=2[CH:20]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)cc21
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(3,5-di-t-butyl-4-hydroxyphenoxy)phenyl}-N-methylcarbamate (0.72 g) and 4N hydrogen chloride/dioxane (20 ml) was stirred at room temperature for 17 hours. The solvent of the reaction mixture was evaporated to dryness. To the residue was added ethyl acetate and insoluble product was isolated by filtration and washed with ethyl acetate to give the title compound (0.41 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11](Br)[C:7]([O:8][CH2:9][CH3:10])=[CH:6][C:5]=1Br)[CH3:2].[Li].[CH3:16][Si:17](Cl)([CH3:19])[CH3:18].C(Br)CCC>O.CO>[CH2:1]([O:3][C:4]1[CH:12]=[C:11]([Si:17]([CH3:19])([CH3:18])[CH3:16])[C:7]([O:8][CH2:9][CH3:10])=[CH:6][C:5]=1[Si:17]([CH3:19])([CH3:18])[CH3:16])[CH3:2]
Reactant: CCOc1cc(Br)c(OCC)cc1Br
Reactant: C[Si](C)(C)Cl
Agent: [Li]
Solvent: CO
Solvent: CCCCBr
Solvent: O
Product: CCOc1cc([Si](C)(C)C)c(OCC)cc1[Si](C)(C)C
Temperature: 35 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
To 32.4 g (0.1 mol) of 2,5-dibromohydroquinone diethyl ether were successively added 160 ml of diether ether, 2.8 g (0.4 gram-atom) of metallic lithium and 21.7 g (0.2 mol) of trimethylsilyl chloride, and the mixture was stirred under a nitrogen stream at 20° to 23° C. 27.4 g (0.2 mol) of butyl bromide was added dropwise to the mixture over a period of 1 hour, and the stirring was continued for an additional one hour while heating at 35° C. After cooling with ice, 50 ml of methanol was added thereto, followed by stirring. The reaction mixture was poured into water, and was extracted with 200 ml of ethyl acetate. The ethyl acetate layer was washed with 200 ml of a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness and crystallized from acetonitrile. Recrystallization from acetonitrile gave 15.5 g (yield: 50%) of 2,5-bis(trimethylsilyl)hydroquinone diethyl ether having a melting point of 129° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C:9]2=[O:14])=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[ClH:38].[N:39]12[CH2:46][CH2:45][CH:42]([CH2:43][CH2:44]1)[C@@H:41]([NH:47][C:48]([C:50]1[S:51][C:52]3[C:58](Br)=[CH:57][CH:56]=[CH:55][C:53]=3[CH:54]=1)=[O:49])[CH2:40]2.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:38].[N:39]12[CH2:44][CH2:43][CH:42]([CH2:45][CH2:46]1)[C@@H:41]([NH:47][C:48]([C:50]1[S:51][C:52]3[C:58]([C:2]4[CH:7]=[CH:6][C:5]([N:8]5[CH2:13][CH2:12][O:11][CH2:10][C:9]5=[O:14])=[CH:4][CH:3]=4)=[CH:57][CH:56]=[CH:55][C:53]=3[CH:54]=1)=[O:49])[CH2:40]2
Reactant: O=C1COCCN1c1ccc(Br)cc1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3ccc(N4CCOCC4=O)cc3)c2s1

Procedure:
120 mg (0.39 mmol) of 4-(4-bromophenyl)-3-morpholinone, 115.3 mg (0.45 mmol) of bis(pinacolato)diboron, 96.6 mg (0.98 mmol) of potassium acetate, 11.1 mg (0.02 mmol) of PdCl2(dppf), 121.6 mg (0.30 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A), 0.76 ml of 2 M sodium carbonate solution and a further 11.1 mg (0.02 mmol) of PdCl2(dppf) in 2 ml of DMF are reacted by general method D. Drying under high vacuum results in 24 mg (16% of theory) of the title compound.