Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH:9]([C:22]1[O:23][CH:24]=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li][C:28](C)(C)C.CI>C1COCC1.CCOC(C)=O>[Si:1]([O:8][CH:9]([C:22]1[O:23][C:24]([CH3:28])=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: [Li]C(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncco1
Solvent: C1CCOC1
Solvent: CI
Solvent: CCOC(C)=O
Product: Cc1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Temperature: -78 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)oxazole (166 mg, 0.444 mmol) was dissolved in anhydrous THF (4 mL), cooled to −78° C. and t-BuLi (1.7 M in pentane, 1.3 equiv) was added dropwise under Ar. The reaction mixture was stirred for 2 h at −40° C., cooled to −78° C. and methyl iodide (3 equiv) was added dropwise and stirred for 1 h. The reaction mixture was warmed to room temperature, diluted with EtOAc, washed with saturated aqueous NaCl and dried over Na2SO4. Evaporation in vacuo yielded the crude product, which was purified by flash chromatography (0-2% EtOAc/hexanes) to afford the title compound as a clear oil (76 mg, 44%): 1H NMR (CDCl3, 600 MHz) δ 7.28-7.25 (m, 2H), 7.17-7.16 (m, 3H), 6.64 (s, 1H), 4.72 (t, 1H, J=7.2 Hz), 2.59 (t, 2H, J=7.8 Hz), 2.29 (s, 3H), 1.90-1.82 (m, 2H), 1.62-1.59 (m, 2H), 1.43-1.34 (m, 6H), 0.88 (s, 9H), 0.08 (s, 3H), −0.04 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 164.9, 143.7, 139.3, 129.2, 129.1, 126.4, 123.2, 69.5, 37.2, 36.8, 32.3, 30.0, 26.6, 26.6, 26.0, 19.1, 11.7, −4.2, −4.3.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([S:13](Cl)(=[O:15])=[O:14])[CH2:11][CH3:12].[C:17]1([S:23]([N:26]2[C:30]3=[N:31][CH:32]=[C:33]([NH:42][C:43](=[O:47])[CH2:44][C:45]#[N:46])[C:34]([NH:35][CH:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)=[C:29]3[CH:28]=[CH:27]2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[C:17]1([S:23]([N:26]2[C:30]3=[N:31][CH:32]=[C:33]([NH:42][C:43](=[O:47])[CH2:44][C:45]#[N:46])[C:34]([NH:35][CH:36]4[CH2:41][CH2:40][N:39]([S:13]([CH2:10][CH2:11][CH3:12])(=[O:15])=[O:14])[CH2:38][CH2:37]4)=[C:29]3[CH:28]=[CH:27]2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#CCC(=O)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCNCC1
Reactant: CCCS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCS(=O)(=O)N1CCC(Nc2c(NC(=O)CC#N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Diisopropylethylamine (0.107 ml, 0.615 mmol) and 1-propanesulfonyl chloride (0.035 ml, 0.308 mmol) were added sequentially to a solution of N-[1-benzenesulfonyl-4-(piperidin-4-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-cyano-acetamide (hydrochloride salt) (0.205 mmol) in CH2Cl2 (2 ml) at 25° C. The reaction mixture was stirred for 3 h at 25° C., then was partitioned between saturated NaHCO3 (6 ml) and CH2Cl2 (2 ml). The phases were separated using a phase separation column (Biotage) and the organic layer was concentrated under reduced pressure to give crude N-{1-benzenesulfonyl-4-[1-(propane-1-sulfonyl)-piperidin-4-ylamino]-1H-pyrrolo[2,3-b]pyridin-5-yl}-2-cyano-acetamide as a brown oil/solid. LCMS (Method G, ESI): RT=0.88 min, m+H=545.3. This material was used in the next step below without additional purification or characterization.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[Mg+2].FC(F)(F)S([O-])(=O)=O.[CH:18]([Si:21]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[O:22][CH2:23][C@@H:24]([OH:26])[CH3:25])([CH3:20])[CH3:19].[O:33]1[CH2:35][C@@H:34]1[C:36]([O:38][CH3:39])=[O:37]>C(OCC)(=O)C>[OH:33][C@H:34]([CH2:35][O:26][C@@H:24]([CH3:25])[CH2:23][O:22][Si:21]([CH:18]([CH3:20])[CH3:19])([CH:27]([CH3:29])[CH3:28])[CH:30]([CH3:32])[CH3:31])[C:36]([O:38][CH3:39])=[O:37]
Reactant: COC(=O)[C@H]1CO1
Reactant: CC(C)[Si](OC[C@H](C)O)(C(C)C)C(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Mg+2]
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](O)CO[C@@H](C)CO[Si](C(C)C)(C(C)C)C(C)C
Temperature: 80 °C
Reaction time: 48 h
Yield: 41.2 %

Procedure:
Magnesium trifluoromethanesulfonate (1.263 g, 3.92 mmol) was added to a mixture of (S)-1-(triisopropylsilyloxy)propan-2-ol (4.55 g, 19.59 mmol) and (R)-methyl oxirane-2-carboxylate (2 g, 19.59 mmol) in ethyl acetate (40 mL). The resulting suspension was heated to 80° C. for 72 hours. Further (R)-methyl oxirane-2-carboxylate (2 g, 19.59 mmol) was added and the mixture stirred at 80° C. for 48 hrs. Further (R)-methyl oxirane-2-carboxylate (2 g, 19.59 mmol) was added and the mixture stirred for 24 hrs. The mixture was allowed to cool, filtered through a bed of silica (˜10 g), washed through with EtOAc and evaporated. The crude product was purified by flash silica chromatography, elution gradient 10 to 50% EtOAc in isohexane, to afford the product (2.7 g, 41%).
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[N:26](C3CCCCO3)[N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH3:33][C:34]1([OH:38])[CH2:37][NH:36][CH2:35]1>>[OH:38][C:34]1([CH3:33])[CH2:37][N:36]([C:2]2[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)=[CH:20][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=3)=[O:7])=[CH:4][N:3]=2)[CH2:35]1
Reactant: CC1(O)CNC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Product: CC1(O)CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2ccn[nH]2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 33 using 6-chloro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 32.1) and 3-methylazetidin-3-ol to afford an off-white powder. HPLC (Condition 4) tR=4.52 min, UPLC-MS (Condition 3) tR=0.88 min, m/z=434.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.30 (s, 3H) 3.61 (s, 4H) 5.40 (s, 1H) 6.41 (s, 1H) 7.32 (d, J=8.60 Hz, 2H) 7.74-7.89 (m, 3H) 8.04 (d, J=2.35 Hz, 1H) 8.70 (s, 1H) 10.20 (s, 1H) 12.90-13.15 (m, 1H).
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]([OH:20])=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C.C(Cl)(Cl)(Cl)Cl>[C:2]1([C:1]2[O:20][C:11]3[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:17][CH:18]=[CH:19][C:10]=3[N:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc(NC(=O)c2ccccc2)c1O
Agent: O=C(O)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc2nc(-c3ccccc3)oc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
5.8 ml of CCl4 in 5 ml of acetonitrile were added to 30 mmol of the compound from Example XIV, 30 mmol of benzoic acid, 50 mmol of triphenylphosphine and 120 mmol of triethylamine in 100 ml of acetonitrile at 3° C. under argon in the course of 15 min and the mixture was stirred at room temperature for 20 hours and concentrated, diethyl ether was added to the residue, the solid was filtered off with suction, the filtrate was concentrated and the residue was separated on silica gel. M.p.: 77° C. (white needles)
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19](CCl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27].[CH3:31]N(C)C=O>>[Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[CH:16]3[N:20]=[C:19]([N:28]([CH2:29][CH3:30])[CH2:26][CH3:27])[O:18][N:17]3[CH3:31])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Reactant: CN(C)C=O
Reactant: CCNCC
Product: CCN(CC)C1=NC(c2ncn3c2[C@@H]2CCN2C(=O)c2c(Cl)cccc2-3)N(C)O1
Yield: 96 %

Procedure:
3.76 g (10 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one were stirred at room temperature overnight with 2.19 g (30 mmol) of diethylamine and 30 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with methylene chloride/methanol 19/1 there were obtained 4.5 g (96%) of (S)-8-chloro-1-(5-diethylamino-methyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]-imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride of m.p. 218°-220°.
Reaction SMILES: CO[C:3]([C@@H:5]1[C@@H:12]2[C@@H:8]([O:9][C:10]([CH3:14])([CH3:13])[O:11]2)[C@H:7]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3[NH:24][CH:25]([CH3:27])[CH3:26])[O:6]1)=[O:4].O.[NH2:29][NH2:30]>CO>[CH:25]([NH:24][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[C:21]=1[N:22]=[CH:23][N:15]2[C@H:7]1[C@@H:8]2[O:9][C:10]([CH3:14])([CH3:13])[O:11][C@@H:12]2[C@@H:5]([C:3]([NH:29][NH2:30])=[O:4])[O:6]1)([CH3:26])[CH3:27]
Reactant: COC(=O)[C@H]1O[C@@H](n2cnc3c(NC(C)C)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21
Reactant: NN
Solvent: CO
Solvent: O
Product: CC(C)Nc1ncnc2c1ncn2[C@@H]1O[C@H](C(=O)NN)[C@H]2OC(C)(C)O[C@H]21
Temperature: 25 °C

Procedure:
A mixture of (3aS,4S,6R,6aR)-6-(6-isopropylamino-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxole-4-carboxylic acid methyl ester (3.76 g) and hydrazine hydrate (1.26 ml) in methanol (140 ml) was heated under reflux for 48 h. After cooling to room temperature, the mixture was concentrated in vacuo and the residue triturated with ethyl acetate to afford the title compound as a white solid (3.3 g).
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].C(Cl)Cl.[CH3:18][C:19]1([CH3:52])[NH:24][CH2:23][CH2:22][N:21]([C:25]2[N:26]([CH2:47][C:48]([F:51])([F:50])[F:49])[C:27]3[C:32]([N:33]=2)=[C:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[N:30]=[C:29]([C:40]2[CH:41]=[N:42][C:43]([NH2:46])=[N:44][CH:45]=2)[N:28]=3)[CH2:20]1>C(Cl)Cl.CO>[C:8]([N:24]1[CH2:23][CH2:22][N:21]([C:25]2[N:26]([CH2:47][C:48]([F:51])([F:49])[F:50])[C:27]3[C:32]([N:33]=2)=[C:31]([N:34]2[CH2:35][CH2:36][O:37][CH2:38][CH2:39]2)[N:30]=[C:29]([C:40]2[CH:45]=[N:44][C:43]([NH2:46])=[N:42][CH:41]=2)[N:28]=3)[CH2:20][C:19]1([CH3:52])[CH3:18])(=[O:10])[CH3:9]
Reactant: CC1(C)CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)N1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
Triethylamine (72.8 μl, 0.52 mmol) and acetic anhydride (24.6 μl, 0.26 mmol) were added to a methylene chloride solution (3.0 ml) of 5-[8-(3,3-dimethylpiperazin-1-yl)-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-amine (107.2 mg, 0.22 mmol) with ice cooling. The resulting mixture was stirred at room temperature for 2 hours followed by the addition of acetic anhydride (4.1 μl, 0.04 mmol) with ice cooling and the resulting mixture was stirred at room temperature for 4.5 hours. The reaction mixture was poured into methylene chloride-methanol (10:1), washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by preparative thin layer silica gel chromatography (methylene chloride:methanol=10:1) to give the title compound (102.6 mg, 88%) as a pale yellow solid.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=[C:7]2[C:15]([O:17]CC)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:20]1([NH2:23])[CH2:22][CH2:21]1>C(O)C>[CH:1]1([N:6]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=[C:7]2[C:15]([NH:23][CH:20]2[CH2:22][CH2:21]2)=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NC1CC1
Reactant: CCOC(=O)c1nc2cccnc2n1C1CCCC1
Solvent: CCO
Product: O=C(NC1CC1)c1nc2cccnc2n1C1CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl 3-cyclopentyl-3H-imidazo[4,5-b]pyridine-2-carboxylate (C7) (0.12 g, 0.46 mmol) in ethanol (10 mL) was added cyclopropylamine (0.55 g, 9.6 mmol), and the reaction mixture was stirred at room temperature for 18 hours. After concentration in vacuo, purification was effected via preparative thin layer chromatography on silica gel (Eluent: 5:1 petroleum ether/ethyl acetate) to afford the product as a yellow solid. Yield: 36 mg, 0.13 mmol, 28%. LCMS m/z 270.9 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.47 (dd, J=4.6, 1.5 Hz, 1H), 8.02 (br d, J=8 Hz, 1H), 7.85 (br s, 1H), 7.27 (dd, J=8.2, 4.6 Hz, 1H, assumed; partially obscured by solvent peak), 6.16-6.27 (m, 1H), 2.89-2.97 (m, 1H), 2.51-2.64 (m, 2H), 2.06-2.19 (m, 4H), 1.69-1.81 (m, 2H), 0.87-0.95 (m, 2H), 0.69-0.76 (m, 2H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]=[CH:14][CH:13]=2)[CH:10]=1)[C:6]#[N:7].Cl.Cl[CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl-:22].[NH2:2][C:3]1[CH:10]=[C:9]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N+:15]([CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:14][CH:13]=2)[CH:8]=[C:5]([C:6]#[N:7])[CH:4]=1
Reactant: N#Cc1cc(N)cc(Nc2ccnc3cc(Cl)ccc23)c1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1cc(N)cc(Nc2cc[n+](CCN3CCCCC3)c3cc(Cl)ccc23)c1
Product: [Cl-]
Yield: 88 %

Procedure:
3-Amino-5-[(7-chloroquinolin-4-yl)amino]benzonitrile hydrochloride prepared from step B of example 19 (0.88 g, 2.98 mmol), 1-(2-chloroethyl)piperidine hydrochloride (0.55 g, 1 eq) and K2CO3 (0.83 g, 2 eq) were refluxed in 50 mL of acetonitrile for 48 h. The reaction mixture was then filtered. The filtrate was evaporated to yield expected compound as a yellow powder (0.58 g, 44% yield). m/z (ESI) 406.2 [M]+.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8](=[N:10][OH:11])C.F[C:13]1[CH:20]=[C:19](C#N)C=[CH:17][C:14]=1[C:15]#[N:16].[Cl-].[NH4+:24]>C1COCC1>[NH2:24][C:8]1[C:7]2[CH:17]=[C:14]([C:15]#[N:16])[CH:13]=[CH:20][C:19]=2[O:11][N:10]=1
Reactant: N#Cc1ccc(C#N)c(F)c1
Reactant: CC(C)=NO
Reactant: [NH4+]
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc2onc(N)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a stirring solution of potassium t-butoxide (8.4 g, 75 mmol) in THF (100 mL) was added acetone oxime (5.5 g, 75 mmol). After stirring for 30 min, a solution of 2-fluoroterephthalonitrile (10 g, 68 mmol) in THF (50 mL) was added; and stirring was continued for an additional 2 hr. Saturated aqueous ammonium chloride (100 mL) was added and the solvents were removed in vacuo. The residue was partitioned between EtOAc and brine. The layers were separated and the organic phase was washed once with brine, dried (MgSO4), filtered and concentrated. This crude solid was suspended in a solution of EtOH (150 mL), concentrated HCl (50 mL) and water (100 mL). This mixture was refluxed for 2 h. After cooling to room temperature, the solvents were removed in vacuo. The residue was treated with saturated aqueous sodium bicarbonate (200 mL), and the product was extracted by washing the aqueous layer three times with EtOAc. This organic solution was washed once with brine, dried (MgSO4), filtered and concentrated to give a pink colored solid (9.4 g, 86%).
Reaction SMILES: Br.Br[CH:3]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[C:4]([C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[CH:7]=1)=O.[NH2:20][C:21]([NH2:23])=[S:22].C(N(CC)CC)C>C(#N)C>[CH3:13][C:8]1[CH:7]=[C:6]([C:4]2[N:20]=[C:21]([NH2:23])[S:22][C:3]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:11]=[C:10]([CH3:12])[CH:9]=1
Reactant: NC(N)=S
Reactant: Cc1cc(C)cc(C(=O)C(Br)c2ccncc2)c1
Agent: Br
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(-c2nc(N)sc2-c2ccncc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.4 %

Procedure:
To a solution of 2-bromo-1-(3,5-dimethylphenyl)-2-(4-pyridyl)ethanone hydrobromide (5.0 g, 13 mmol) and thiourea (1.0 g, 14 mmol) in acetonitrile (60 mL) was added dropwise triethylamine (1.9 ml, 14 mmol) and the mixture was stirred at room temperature for 3 h. The solvent was concentrated under reduced pressure and a saturated aqueous sodium hydrogencarbonate solution was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water and the solvent was evaporated. The obtained crude crystals were recrystallized from ethyl acetate to give the title compound (2.0 g, 7.2 mmol, yield 55%).
Reaction SMILES: [ClH:1].[C:2]([O:6][C:7]([NH:9][C@H:10]([C:20]([NH:22][CH2:23][C:24]([NH:26][C@H:27]([C:35]([NH:37][C:38]1[CH:47]=[C:46]2[C:41]([C:42]([CH3:49])=[CH:43][C:44](=[O:48])[O:45]2)=[CH:40][CH:39]=1)=[O:36])[CH2:28][CH2:29][CH2:30][NH:31][C:32](=[NH:34])[NH2:33])=[O:25])=[O:21])[CH2:11][O:12]CC1C=CC=CC=1)=[O:8])([CH3:5])([CH3:4])[CH3:3].[H][H]>CO.[C].[Pd].C(O)(=O)C>[ClH:1].[C:2]([O:6][C:7]([NH:9][C@H:10]([C:20]([NH:22][CH2:23][C:24]([NH:26][C@H:27]([C:35]([NH:37][C:38]1[CH:47]=[C:46]2[C:41]([C:42]([CH3:49])=[CH:43][C:44](=[O:48])[O:45]2)=[CH:40][CH:39]=1)=[O:36])[CH2:28][CH2:29][CH2:30][NH:31][C:32](=[NH:33])[NH2:34])=[O:25])=[O:21])[CH2:11][OH:12])=[O:8])([CH3:5])([CH3:3])[CH3:4]
Reactant: Cc1cc(=O)oc2cc(NC(=O)[C@H](CCCNC(=N)N)NC(=O)CNC(=O)[C@H](COCc3ccccc3)NC(=O)OC(C)(C)C)ccc12
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(=O)oc2cc(NC(=O)[C@H](CCCNC(=N)N)NC(=O)CNC(=O)[C@H](CO)NC(=O)OC(C)(C)C)ccc12
Yield: 66.9 %

Procedure:
7-(Nα -tert-butyloxycarbonyl-O-benzyl-L-serylglycyl-L-arginyl)amino-4-methylcoumarin hydrochloric acid salt (120 mg, 0.28 mM) was dissolved in methyl alcohol (50 ml), and palladium-carbon catalyst (20 mg) was added. Through this mixture hydrogen gas was passed for 4 hours with stirring. The catalyst was removed by filtration and the filtrate was concentrted to yield a solid material. The residue was dissolved in acetic acid (10 ml) and lyophilized to give 7-(Nα-tert-butyloxycarbonyl-L-serylglycyl-L-arginyl)amino-4-methylcoumarin hydrochloric acid salt [X] (70 mg).
Reaction SMILES: [C:1]1([CH2:7][OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[C:12]1[C:13]2[N:14]([CH:19]=[CH:20][N:21]=2)[N:15]=[C:16]([Cl:18])[CH:17]=1.O>C1COCC1>[CH2:7]([O:8][C:12]1[C:13]2[N:14]([CH:19]=[CH:20][N:21]=2)[N:15]=[C:16]([Cl:18])[CH:17]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1ccccc1
Reactant: Clc1cc(Br)c2nccn2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Clc1cc(OCc2ccccc2)c2nccn2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of phenylmethanol (3.35 g, 31 mmol, 1.2 eq) in THF (80 mL), NaH (60% dispersion in mineral oil, 1.34 g, 33.5 mmol, 1.3 eq) is added in portions. The resulting mixture is stirred at RT for 30 min and then 8-bromo-6-chloroimidazo[1,2-b]pyridazine (D-3) (6 g, 25.8 mmol, 1.0 eq) is added. The resulting mixture is stirred at RT for an additional 2 h and then poured into water (30 mL). The mixture is extracted with ethyl acetate (2×100 mL). The combined organic layers are washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo to afford the product, 8-(benzyloxy)-6-chloroimidazo[1,2-b]pyridazine (D-4).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([C:20]#[N:21])=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[NH:7][C:8]=1[C:9]([F:12])([F:11])[F:10].Br[CH2:23]Cl.[CH2:25]([OH:27])[CH3:26]>O1CCCC1>[Br:3][C:4]1[C:5]([C:20]#[N:21])=[C:6]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[N:7]([CH2:23][O:27][CH2:25][CH3:26])[C:8]=1[C:9]([F:12])([F:11])[F:10]
Reactant: CCO
Reactant: N#Cc1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1Br
Reactant: ClCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCn1c(-c2ccc(Cl)cc2)c(C#N)c(Br)c1C(F)(F)F
Reaction time: 3 h
Yield: 91.3 %

Procedure:
A stirred mixture of sodium hydride (26.5 g, 1.105 mol) in tetrahydrofuran, under nitrogen, is treated slowly with a solution of 4-bromo-2-(p-chlorophenyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile (1.00 g, 0.273 mol) in tetrahydrofuran at ≤60° C. When the addition is complete, the reaction mixture is treated with bromochloromethane (93.0 g, 0.718 mol), heated to 63°-65° C., treated dropwise with absolute ethanol (39.5 g, 0.859 mol) over a 5.5 hour period, stirred at 63°-65° C. for another 3 hours and concentrated in vacuo. The concentrate is dispersed in a mixture of water and methylene chloride. The aqueous phase is separated and washed with methylene chloride. The organic phases are combined and concentrated. The concentrate is dispersed in hexane, cooled to 5°-10° C. and filtered. The filtercake is washed with heptane and dried to give the title product as a white solid, 111.6 g, (91.3% yield) and 91.2% purity by HPLC analysis.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[C@@H:10]([C:15]([OH:17])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C@@H:10]([C:15]([OH:17])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@@H](C(=O)O)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)[C@@H](C(=O)O)C1
Reaction time: 18 h
Yield: 63.1 %

Procedure:
In a dry flask (3S,4R)-4-aminopiperidine-1,3-dicarboxylic acid 1-tert-butyl ester (1.32 g, 5.40 mmol) was dissolved in dichloromethane (30 mL) and triethylamine (1.0 mL, 7.2 mmol) and benzyl chloroformate (0.94 mL, 5.9 mmol) were added. The mixture was stirred for 18 hours. Water (30 mL) was added and the layers separated. The aqueous layer was extracted with dichloromethane (30 mL). The combined organic layers were washed with brine, dried with magnesium sulfate, filtered, and concentrated in vacuo to give a crude oil (2.13 g). Purification by flash column chromatography (5-20% methanol/chloroform) provided a colorless oil (1.29 g, 63%). 1H NMR (400 MHz, DMSO-d6, 120° C.), δ: 7.34 (m, 5H), 6.76 (bs, 1H), 5.04 (s, 2H), 4.01, (bs, 1H), 3.78 (dd, J=14, J′=7, 1H), 3.47 (m, 2H), 3.26 (m, 1H), 2.67 (dt, J=7, J′=4, 1H), 2.49 (m, 1H), 1.79 (m, 1H), 1.59 (m, 1H), 1.40 (s, 9H). MS (ESI), m+/z: (M+Na)+=401.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Cl.[Mg].[CH3:11][N:12]([CH3:21])[C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#N.CC[O:24]CC>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][C:16]([C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([N:12]([CH3:21])[CH3:11])[CH:14]=2)=[O:24])[CH:7]=[CH:8][CH:9]=1
Reactant: CN(C)c1cccc(C#N)c1
Reactant: CCOCC
Reactant: ClCc1cccc(Cl)c1
Agent: [Mg]
Product: CN(C)c1cccc(C(=O)Cc2cccc(Cl)c2)c1
Product: Cl
Reaction time: 8 h

Procedure:
A solution of 10.0 g of 3-chlorobenzyl chloride in 100 ml of dry ether was added slowly to 2.26 g of magnesium in 75 ml of dry ether under nitrogen. The Grignard reagent was stirred at ambient temperature for one hour and then added to a solution of 4.5 g of 3-dimethylaminobenzonitrile in 150 ml of dry ether. After the addition a catalytic amount of CuBr was added and the solution stirred overnight. The reaction was quenched with 200 ml of ammonium chloride solution and diluted with water. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by flash chromatography (silica gel: 8:1 hexane-ethyl acetate) and then treated with ethereal HCl until acidic to wet litmus paper. The precipitate was collected and recrystallized from ethanol-ether to give 3.8 g of 2-(3-chlorophenyl)1-[3-(dimethylamino)phenyl]ethanone hydrochloride, m.p. 92°-94° C.