Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]([CH3:23])[C:4]([C:13]2[S:14][C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH2:22])[C:20]=3[N:21]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.C(N(CC)CC)C.[C:31]([C:33]1([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)#[CH:32]>[Cu]I.CN(C=O)C>[NH2:39][C:33]1([C:31]#[C:32][C:2]2[N:3]([CH3:23])[C:4]([C:13]3[S:14][C:15]4[N:16]=[CH:17][N:18]=[C:19]([NH2:22])[C:20]=4[N:21]=3)=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:6]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: Cn1c(Br)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1
Reactant: C#CC1(N)CCCCC1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(C#CC2(N)CCCCC2)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1
Temperature: 90 °C
Yield: 41 %

Procedure:
A mixture of 2-(2-bromo-1-methyl-4-phenyl-1H-imidazol-5-yl)[1,3]thiazolo[5,4-d]pyrimidin-7-amine (Example 26) (0.02 g), PdCl2dppf (3.5 mg), triethylamine (0.1 mL), DMF (5 mL), copper(I) iodide (1 mg) and 1-ethynylcyclohexylamine (0.034 mL) was heated at 90° C., under an inert atmosphere, for 1.5 hours. The solvent was evaporated in vacuo then purification by flash chromatography on silica eluting with DCM:MeOH (9:1) gave the title compound as a beige solid (9 mg, 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[O:14][C:15]([CH3:20])([CH3:19])[CH2:16][C:17](=[O:18])[C:11]2=[CH:10][C:9]=1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.C1(N[S:50]([C:53]([F:56])([F:55])[F:54])(=[O:52])=[O:51])C=CC=CC=1>CN(C=O)C>[F:54][C:53]([F:56])([F:55])[S:50]([O:18][C:17]1[C:11]2[C:12](=[N:13][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[C:9]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)[CH:10]=2)[O:14][C:15]([CH3:20])([CH3:19])[CH:16]=1)(=[O:52])=[O:51]
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Reactant: CC1(C)CC(=O)c2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nc2O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC1(C)C=C(OS(=O)(=O)C(F)(F)F)c2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nc2O1
Reaction time: 0.08 h

Procedure:
To the product of Example 3 (0.47 g, 1.2 mmol) in DMF (9 mL) at −78° C., was added 1 M LiHMDS in THF (1.3 mL, 1.3 mmol) and the reaction was stirred for 5 min. N-phenyl trifluoromethanesulfonamide (0.47 g, 1.3 mmol) was added and the reaction was allowed to come to rt. The reaction was stirred an additional 15 min, concentrated and the residue was purified by flash chromatography on silica gel gradient eluted with 0-20% EtOAc in hexane to afford the title compound. Step B: 7-(2-Chlorophenyl)-6-(4-chlorophenyl)-2,2-dimethyl-4-pyridin-4-yl-2H-pyrano[2,3-b]pyridine
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][C:8]1[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:10][N:11]([CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[CH:12]=1)=[O:5])[CH3:2].[F:29][C:30]([F:40])([F:39])[C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1.O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C>O.CN(C)C=O>[C:23]1([C:9]2[C:8]([CH2:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:12][N:11]([CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:36][CH2:35][C:34]4[CH:33]=[CH:32][C:31]([C:30]([F:29])([F:39])[F:40])=[CH:38][CH:37]=4)=[O:19])=[CH:16][CH:15]=3)[N:10]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(C(=O)O)cc2)nc1-c1ccccc1
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(C(=O)NCc3ccc(C(F)(F)F)cc3)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 77.7 %

Procedure:
A mixture of 4-[4-(2-ethoxycarbonylethyl)-3-phenyl-1H-pyrazol-1-ylmethyl]benzoic acid (500 mg), 4-trifluoromethylbenzylamine (250 mg), 1-hydroxybenzotriazole monohydrate (210 mg), WSC (270 mg), and N,N-dimethylformamide (10 ml) was stirred at room temperature for 13 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium bicarbonate solution, 1 N hydrochloric acid, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-phenyl-1-[4-(4-trifluoromethylbenzylaminocarbonyl)benzyl]-1H-pyrazol-4-yl]propionate (550 mg, yield: 77%) was obtained as a colorless amorphous substance from the fraction eluted with ethyl acetate-hexane (3:1, volume ratio).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9]([C:12]2[CH:20]=[C:19]3[C:15]([C:16]([CH2:28][CH3:29])=[N:17][N:18]3[C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:14][CH:13]=2)=[CH:8][CH2:7]1)=[O:5])C.O1CCCC1.[OH-].[Na+]>CO>[CH2:28]([C:16]1[C:15]2[C:19](=[CH:20][C:12]([C:9]3[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH:8]=3)=[CH:13][CH:14]=2)[N:18]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[N:17]=1)[CH3:29]
Reactant: CCOC(=O)C1CC=C(c2ccc3c(CC)nn(-c4ccc(F)cc4)c3c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1nn(-c2ccc(F)cc2)c2cc(C3=CCC(C(=O)O)CC3)ccc12
Reaction time: 3 h
Yield: 29.6 %

Procedure:
To a stirred solution of 1.13 g (2.87 mmol) of 4-(3-ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl)-cyclohex-3-ene-carboxylic acid ethyl ester dissolved in 50 mL of methanol and 15 mL of tetrahydrofuran was added 8.62 mL (8.61 mmol) of 1N sodium hydroxide and reaction mixture heated to reflux for 3 hr. After 3 hr, the reaction mixture was concentrated on a rotary evaporator, diluted with 200 mL of H2O, acidified to pH 1 with 1N HCl and extracted 2×200 mL ethyl acetate. The organic extracts were combined, washed with water, brine and dried over Na2SO4. Filtration, concentration and drying gave crude product. Recrystallization from ethyl acetate/hexane gave 0.31 grams of white crystalline product. mp=214-216° C.; MS, m/z 365 (M+H+, base).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:53]/[O:54][C:55]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])([CH3:57])[CH3:56])/[C:27]([NH:29][CH:30]2[C:51](=[O:52])[N:32]3[C:33]([C:39]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37]Cl)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:65][C:66]1[S:67][C:68]2[C:69]([N:74]=1)=[N:70][CH:71]=[CH:72][CH:73]=2.SC1SC2C=CN=CC=2N=1>>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:53]/[O:54][C:55]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])([CH3:57])[CH3:56])/[C:27]([NH:29][CH:30]2[C:51](=[O:52])[N:32]3[C:33]([C:39]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37][S:65][C:66]4[S:67][C:68]5[C:69]([N:74]=4)=[N:70][CH:71]=[CH:72][CH:73]=5)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Reactant: Sc1nc2ncccc2s1
Agent: Sc1nc2cnccc2s1
Product: COc1ccc(COC(=O)C2=C(CSc3nc4ncccc4s3)CS[C@@H]3C(NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Yield: 60.6 %

Procedure:
Using 276 mg of p-methoxybenzyl 7-{(Z)-2-(2-tritylaminothiazol-4-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido}-3-chloromethyl-3-cephem-4-carboxylate and 60 mg of 2-mercaptothiazolo[4,5-b]pyridine in place of p-methoxybenzyl 7-{(Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido}-3-chloromethyl-3-cephem-4-carboxylate and 2-mercaptothiazolo[4,5-c]pyridine, respectively, the reaction and purification were carried out in the same manner as in Example 1(a) to obtain 191 mg of the title compound in a yield of 61%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]2=[N:17][CH:18]=[N:19][C:20]([NH:21][CH:22]3[CH2:26][CH2:25][NH:24][CH2:23]3)=[C:15]2[CH:14]=[N:13]1.[CH:27]([O:30][C:31](Cl)=[O:32])([CH3:29])[CH3:28].C(N(CC)CC)C>CN(C=O)C>[CH:27]([O:30][C:31]([N:24]1[CH2:25][CH2:26][CH:22]([NH:21][C:20]2[N:19]=[CH:18][N:17]=[C:16]3[N:12]([C:3]4[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:9])=[O:10])=[CH:7][C:2]=4[F:1])[N:13]=[CH:14][C:15]=23)[CH2:23]1)=[O:32])([CH3:29])[CH3:28]
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(NC4CCNC4)ncnc32)c(F)c1
Reactant: CC(C)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)OC(=O)N1CCC(Nc2ncnc3c2cnn3-c2ccc(S(C)(=O)=O)cc2F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.5 %

Procedure:
A mixture of [1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-pyrrolidin-3-yl-amine (20 mg, 0.048 mmol), isopropylchloroformate (7.2 μL, 0.52 mmol), and triethylamine (20 μL, 0.144 mmol) in DMF (500 μL) was stirred for 2 hours at room temperature. The reaction was purified by HPLC to afford compound A142 as a white solid (9 mg, 41%). Exact mass calculated for C20H23FN6O4S 462.15 found 463.3 (MH+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]([Br:24])(Br)Br.OC[C:27]1[O:28][C:29](=[O:44])[C:30]2[C:35]([C:36]=1[C:37]1[CH:38]=[C:39]([CH3:43])[CH:40]=[CH:41][CH:42]=1)=[CH:34][CH:33]=[CH:32][CH:31]=2>CN(C=O)C>[Br:24][CH2:21][C:27]1[O:28][C:29](=[O:44])[C:30]2[C:35]([C:36]=1[C:37]1[CH:38]=[C:39]([CH3:43])[CH:40]=[CH:41][CH:42]=1)=[CH:34][CH:33]=[CH:32][CH:31]=2
Reactant: BrC(Br)(Br)Br
Reactant: Cc1cccc(-c2c(CO)oc(=O)c3ccccc23)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cccc(-c2c(CBr)oc(=O)c3ccccc23)c1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
Triphenylphosphine (270 mg, 1.030 mmol) and perbromomethane (342 mg, 1.030 mmol) were added to a solution of 3-(hydroxymethyl)-4-m-tolyl-1H-isochromen-1-one (intermediate B5, 211 mg, 0.792 mmol) in DMF (2 ml), and the resulting mixture was stirred at RT. The reaction was then purified via reverse phase chromatography with a Biotage C18 30 g SNAP column (Phase A, water 95%, ACN 4.5%, formic acid 0.5%; Phase B ACN 99.5%, formic acid 0.5%) to give the title compound (192 mg, 73.6%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[N:11]=[C:12]([NH2:23])[N:13]=[C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[N:11]=[C:12]([NH2:23])[N:13]=[C:14]([N:17]4[CH2:18][CH2:19][N:20]([S:36]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)(=[O:38])=[O:37])[CH2:21][CH2:22]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3ccc(F)cc3)sc2n1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Nc1nc(N2CCN(S(=O)(=O)c3ccccc3)CC2)c2nc(-c3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.3 %

Procedure:
To a solution of 2-(4-fluorophenyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine (50 mg, 0.15 mmol) and pyridine (18 μl, 0.23 mmol) in DMF (1 ml) was added benzenesulfonyl chloride (21 μl, 0.17 mmol). The reaction mixture was stirred for 3 hours at room temperature. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4. After removing the solvents, the crude residue was purified by flash chromatography on silica (CH2Cl2/MeOH 80:1) to yield the title compound as a white solid (32 mg, 45%).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:17][O:18][CH2:19][CH2:20]Br.O>CN(C)C=O>[CH3:17][O:18][CH2:19][CH2:20][N:14]1[CH2:15][CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:10][CH2:11][CH2:12][C:13]1=[O:16]
Reactant: O=C1CCCC(c2ccccc2)CN1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCN1CC(c2ccccc2)CCCC1=O
Temperature: 25 °C
Reaction time: 21 h

Procedure:
Sodium hydride (60% dispersion in mineral oil; 0.32 g, 8.03 mmol) was added to a solution of 6-phenylazepan-2-one (0.76 g, 4.02 mmol) in N,N-dimethylformamide (15 mL) at 0° C., followed by the addition of 2-bromoethyl methyl ether (0.837 g, 6.03 mmol), and the mixture was allowed to warm to ambient temperature. After 21 h, water was added and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water (3×), saturated brine, dried over sodium sulfate, filtered and concentrated. MS 248 (M+1).
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][C:11]([C:13]2[S:14][CH:15]=[C:16](Br)[N:17]=2)=[O:12])=[C:8]([CH3:19])[C:7]([O:20][CH3:21])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:22]([Si:24]([CH3:27])([CH3:26])[CH3:25])#[CH:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(C)C)(C)C>C(NC(C)C)(C)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([C:4]1[C:9]([NH:10][C:11]([C:13]2[S:14][CH:15]=[C:16]([C:23]#[C:22][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:17]=2)=[O:12])=[C:8]([CH3:19])[C:7]([O:20][CH3:21])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccc(C(C)=O)c(NC(=O)c2nc(Br)cs2)c1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)OC(C)C
Solvent: CC(C)NC(C)C
Product: COc1ccc(C(C)=O)c(NC(=O)c2nc(C#C[Si](C)(C)C)cs2)c1C
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 84 %

Procedure:
To a suspension of compound 207b (10.12 g, 1 eq.) in diisopropylamine (40 mL) were added ethynyltrimethylsilane (5.7 mL, 1.5 eq.), triphenylphosphine (0.283 g, 0.04 eq.), copper iodide (0.206 g, 0.04 eq.), and PdCl2(PPh3)2 (0.38 g, 0.02 eq.). The mixture was stirred under nitrogen and heated to 80° C. (external temperature). After 10 min, the solvent was refluxed, and the mixture solidified and turned brown grey. DIPA (20 mL) was added to solubilize the reaction mixture. After 2.5 hrs, the reaction was complete and the mixture cooled down to room temperature. Diisopropyl ether (20 mL) was added. A grey solid was recovered by filtration, dissolved in dichloromethane, and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated to give black solid. The residue was purified by chromatography on silica gel (dichloromethane) to give compound 208b as a beige solid in 84% yield. 1H NMR (CDCl3, 400 MHz) δ (ppm) 0.29 (s, 9H), 2.13 (s, 3H), 2.58 (s, 3H), 3.93 (s, 3H), 6.81 (d, J=8.78 Hz, 1H), 7.69 (s, 1H), 7.76 (d, J=8.78 Hz, 1H), 11.05 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1([C:10]([OH:12])=O)[CH2:9][CH2:8]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.Cl.[NH2:48][C:49]1[CH:50]=[CH:51][C:52]([N:56]2[CH2:61][CH2:60][CH2:59][C@@H:58]([C:62]([N:64]3[CH2:68][CH2:67][CH2:66][CH2:65]3)=[O:63])[CH2:57]2)=[N:53][C:54]=1[NH2:55]>ClCCl>[NH2:55][C:54]1[C:49]([NH:48][C:10]([C:7]2([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)[CH2:8][CH2:9]2)=[O:12])=[CH:50][CH:51]=[C:52]([N:56]2[CH2:61][CH2:60][CH2:59][C@@H:58]([C:62]([N:64]3[CH2:68][CH2:67][CH2:66][CH2:65]3)=[O:63])[CH2:57]2)[N:53]=1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: O=C(O)C1(c2cnccn2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1NC(=O)C1(c2cnccn2)CC1
Reaction time: 0.17 h
Yield: 34.3 %

Procedure:
To a solution of 1-(pyrazin-2-yl)cyclopropanecarboxylic acid (0.11 g, 0.669 mmol) in anhydrous dichloromethane (15 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (HATU) (0.3 g, 0.803 mmol) and diisopropylethylamine (0.35 mL, 2 mmol) at room temperature. The mixture was stirred for 10 min and then (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (0.29 g, 0.803 mmol) was added. The reaction mixture was stirred for 30 min. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via column chromatography (100-200 mesh silica gel, 0-5% methanol in dichloromethane) to afford (R)—N-(2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)-1-(pyrazin-2-yl)cyclopropanecarboxamide (100 mg). MS (ES+APCI) (M+H) 436.1.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([N:18]1[C:23](=[O:24])[C:22]2[CH:25]=[CH:26][S:27][C:21]=2[N:20]=[C:19]1[CH:28]([NH:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[CH2:29][CH3:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>ClCCl>[CH2:11]([N:18]1[C:23](=[O:24])[C:22]2[CH:25]=[CH:26][S:27][C:21]=2[N:20]=[C:19]1[CH:28]([N:31]([CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:29][CH3:30])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CCC(NCCN(C)C)c1nc2sccc2c(=O)n1Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(c1nc2sccc2c(=O)n1Cc1ccccc1)N(CCN(C)C)C(=O)c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
A solution of 4-bromobenzoyl chloride (8 mg, 0.035 mmol, 1 equiv) in dichloromethane (1 mL) was added to a solution of 3-benzyl-2-(1-{[2-(dimethylamino)ethyl]amino}propyl)thieno[2,3-d]pyrimidin-4(3H)-one (3-1, 13 mg, 0.035 mmol, 1 equiv) and N,N-diisopropylethylamine (5 mg, 0.035 mmol, 1 equiv) in dichloromethane (1 mL), and the resulting mixture was stirred under ambient conditions for 1 h. The reaction mixture was washed with saturated aqueous NaHCO3 solution, and brine, then dried (MgSO4) and concentrated. The residue was purified by flash chromatography. Elution with CH2Cl2 to 5% NH3-EtOH/CH2Cl2 gave N-[1-(3-benzyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)propyl]-4-bromo-N-[2-(dimethylamino)ethyl]benzamide (3-2) as an off-white foam. 1H NMR (500 MHz, CDCl3) δ 7.53 (m, 3H), 7.31 (m, 5H), 7.14 (m, 2H), 6.09 (d, J=15.6 Hz, 1H), 5.94 (m, 1H), 5.10 (d, J=15.6 Hz, 1H), 3.40 (m, 2H), 2.11 (m, 1H), 2.03 (m, 2H), 1.87 (m, 1H), 1.79 (s, 6H), 0.66 (t, J=6.6 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3[CH:14]=[CH:15][C:16]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][C:12]=3[O:11][C:10]([CH3:24])([CH3:23])[C:9]2=O)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>O1CCOCC1.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3[CH:14]=[CH:15][C:16]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][C:12]=3[O:11][C:10]([CH3:24])([CH3:23])[C:9]2=[S:35])=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)Oc2cc(NS(C)(=O)=O)ccc2N(c2ccc(F)cc2)C1=O
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CC1(C)Oc2cc(NS(C)(=O)=O)ccc2N(c2ccc(F)cc2)C1=S
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.2 %

Procedure:
To a suspension of N-[4-(4-fluorophenyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide (compound of Example 9, 182 mg) in dioxane (10 mL) was added Lawesson's reagent (202 mg), and the mixture was stirred at room temperature for 2 hours and then stirred at 40° C. for 24 hours. The reaction mixture was diluted with chloroform and the mixture was filtered through a NH-silica gel pad and washed with ethyl acetate. The filtrate and the washings were combined and concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (solvent; n-hexane/ethyl acetate=19/1→3/2) to give N-[4-(4-fluorophenyl)-2,2-dimethyl-3-thioxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl]methanesulfonamide (25 mg) as a yellow powder.
Reaction SMILES: CS(OS(C)(=O)=O)(=O)=O.[CH3:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:14]O.C(N(C(C)C)CC)(C)C.[CH3:30][O:31][C:32](=[O:55])[C@H:33]([CH2:42][C:43]1[N:47]=[CH:46][N:45](C(OC(C)(C)C)=O)[CH:44]=1)[NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>ClCCl>[CH3:30][O:31][C:32](=[O:55])[C@H:33]([CH2:42][C:43]1[N:47]([CH2:14][C:13]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:11]([CH3:10])[CH:12]=2)[CH:46]=[N:45][CH:44]=1)[NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:36]
Reactant: COc1ccc(CO)cc1C
Reactant: COC(=O)[C@H](Cc1cn(C(=O)OC(C)(C)C)cn1)NC(=O)OC(C)(C)C
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1cncn1Cc1ccc(OC)c(C)c1)NC(=O)OC(C)(C)C
Temperature: -25 °C
Reaction time: 24 h

Procedure:
A solution of 10.8 g methanesulfonic anhydride in 120 mL dichloromethane is chilled to -50° C. and treated dropwise with a solution of 9.4 g 3-methyl-4-methoxybenzyl alcohol, 10.8 mL diisopropylethylamine and 80 mL dichloromethane. The resulting solution is warmed to -25° C. over 30 min and treated dropwise with 20.0 g N,1-bis-BOC-histidine methyl ester dissolved in 125 mL dichloromethane. The mixture is then allowed to warm to 25° C. over 4 hr, stirring at this temperature 24 hr. The reaction mixture is poured into 700 mL 0.25M, pH=7 potassium phosphate buffer and the organic layer is separated, dried and evaporated. Chromatography on silica gel, eluting with chloroformmethanol (99:1) gives 3-(3-methyl-4-methoxyphenyl)methyl-N-BOC-histidine methyl ester as a gum. NMR (CDCl3) 1.43 (s,9H,t-Bu).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[C:4]([O:11][CH2:12][CH3:13])[C:3]=1[F:14].[Cu][C:16]#[N:17].C(OCC)(=O)C.[NH4+]>CN(C)C=O>[CH2:12]([O:11][C:4]1[C:3]([F:14])=[C:2]([CH:7]=[CH:6][C:5]=1[O:8][CH2:9][CH3:10])[C:16]#[N:17])[CH3:13]
Reactant: N#C[Cu]
Reactant: CCOc1ccc(Br)c(F)c1OCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1ccc(C#N)c(F)c1OCC
Temperature: 155 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
To a solution of 1-bromo-3,4-diethoxy-2-fluorobenzene (12.0 g, 45.6 mmoL) in N,N-dimethylformamide (DMF) (60 mL), copper (I) cyanide (6.8 g, 68.3 mmoL) was added at room temperature and then stirred at 155° C. for 3 hours. After ice cooling the reaction solution, ethyl acetate and 28% aqueous ammonium were added thereto to separate the organic layer. This organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated. The residue was purified by silica gel column chromatography (n-hexane, ethyl acetate) to give 9.0 g of the captioned compound (yield: 94.3%).