Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([NH:14][CH2:15][CH2:16][NH:17][C:18]2[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([O:25][C:26]3[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][C:27]=3[CH3:34])[C:19]=2[CH3:35])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>C1COCC1.CO.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:14][CH2:15][CH2:16][NH:17][C:18]2[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([O:25][C:26]3[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][C:27]=3[CH3:34])[C:19]=2[CH3:35])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC(=O)NCCNc2cc(C)nc(Oc3c(C)cc(C)cc3C)c2C)cc1OC
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(CCNCCNc2cc(C)nc(Oc3c(C)cc(C)cc3C)c2C)cc1OC

Procedure:
Add BH3 in THF (1 M solution, 0.3 mmol, 0.3 mL) to a solution of the crude 2-(3,4-dimethoxyphenyl)-N-(2-{[3,6-dimethyl-2-(2,4,6-trimethylphenoxy)(4-pyridyl)]amino}ethyl) acetamide in THF (2.0 mL) at ambient temperature. Heat the reaction mixture under reflux for 15 h, dilute with a solution of 10% aq HCV/MeOH (1:1, 2 mL) and heat again under reflux (1 h). Dilute the reaction mixture with CHCl3 (10 mL), wash with saturated aq NaHCO3 (1×5 mL), dry and concentrate in vacuo. Chromatograph the crude residue on SiO2-gel using a gradient of 100% EtOAc to 10% Et2NH/EtOAc to obtain the title compound as a colorless oil. Immediately dissolve the product in Et2O (1 mL), treat with excess 4 M HCl/dioxane and concentrate in vacuo to obtain the hydrochloride salt of the title compound as a colorless solid. 1H NMR (d4-MeOH, Unity 400): d 6.99–6.77 (6H, m), 3.81 (3H, s), 3.78 (3H, s), 3.62 (2H, m), 2.98 (2H, t), 2.39 (3H, s), 2.29 (3H, s), 2.16 (3H, s), 2.07 (6H, s). M+1: 464.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7](O)(=O)/[CH:8]=[CH:9]/[CH2:10][CH2:11][CH:12]=[CH2:13].C(N(CC)CC)C.COP([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])(OC)=O.[H-].[Na+].[Cl-].[NH4+]>O.C(COC)OC.C1(C)C=CC=CC=1>[C@H:11]12[CH2:12][C:13](=[CH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C@H:7]1[CH:8]=[CH:9][CH2:10]2
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Reactant: C=CCC/C=C/C(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C=C1C[C@@H]2CC=C[C@H]12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Oxalyl chloride (10 mL) was added dropwise to a toluene solution (60 mL) of (2E)-hepta-2,6-dienoic acid (3.27 g, 25.9 mmol) under ice cooling. The mixture was stirred for 20 minutes, then removed from the ice water bath, and gradually heated to room temperature. After stirring for 50 minutes, the reaction solution was stirred for 1 hour under heating to reflux. The solution was allowed to cool, and the solvent was then distilled off under reduced pressure. To the residue, toluene was further added, and the solvent was then distilled off again under reduced pressure. The residue was dissolved in toluene (20 mL), and this solution was added dropwise over 1 hour to a toluene solution (20 mL) of triethylamine (9.19 g, 91 mmol) heated in advance to 90° C. After completion of the dropwise addition, the mixture was further heated with stirring for 2 hours. The reaction solution was cooled, then diluted with saturated saline and water, and filtered through Celite. The filtrate was separated into organic and aqueous layers. The organic layer was then washed with 1 N hydrochloric acid, then dried over magnesium sulfate, and filtered. This filtrate was added to a reaction solution prepared in advance from a dimethoxyethane solution (20 mL) of tert-butyl dimethoxyphosphorylacetate (5.98 g, 25.9 mmol) and sodium hydride (>65% oil, 986.7 mg, 25.9 mmol), and the mixture was stirred for 1.5 hours. To the reaction solution, a saturated aqueous solution of ammonium chloride, saturated saline, and water were added in this order, and the reaction solution was subjected to extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then filtered. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the compound of interest as a pale yellow oil substance (1.73 g, 32%, E/Z mixture).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]2[CH:11]=[C:10]([C:12]3[N:13]=[N:14][N:15]([CH3:17])[N:16]=3)[CH:9]=[CH:8][C:5]=2[S:6][CH:7]=1.[C-:18]#[N:19].[Na+].O>CS(C)=O>[C:18]([CH2:2][C:3]1[C:4]2[CH:11]=[C:10]([C:12]3[N:13]=[N:14][N:15]([CH3:17])[N:16]=3)[CH:9]=[CH:8][C:5]=2[S:6][CH:7]=1)#[N:19]
Reactant: [C-]#N
Reactant: Cn1nnc(-c2ccc3scc(CBr)c3c2)n1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cn1nnc(-c2ccc3scc(CC#N)c3c2)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 51.4 %

Procedure:
The crude 3-bromomethyl-5-(2-methyl-tetrazol-5-yl)benzo[b]thiophene (0.145 g) in DMSO (0.3 ml) was added to a mixture of sodium cyanide (29.9 mg, 0.6 mmol) in DMSO (0.2 ml) and the mixture was stirred at 100° C. for 2 h. After cooling, the mixture was poured into water (10 ml) and a brown solid was filtered off, washed with water and dried in a vacuum pistol to leave 73.5 mg. The filtrate was extracted with dichloromethane (3×30 ml) and the combined extracts were dried (Na2SO4) and evaporated in vacuo to leave 44.7 mg. This was combined with the original solid and chromatographed on flash silica, eluting with 20-50% ethyl acetate/petroleum ether to yield 61.5 mg (38%) of the title product as a white solid. δ (CDCl3) 3.99 (2H, s), 4.43 (3H, s), 7.59 (1H, s), 8.00 (1H, d, J=8.5 Hz), 8.19 (1H, dd, J=8.5 and 1.5 Hz), 8.47 (1H, s).
Reaction SMILES: [C:1]([C:5]1([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:12][C:8]2=[CH:9][S:10][CH:11]=[C:7]2[CH2:6]1)([O:3]C)=[O:2].[OH-].[K+]>C(O)C.O.O1CCCC1>[C:1]([C:5]1([S:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH2:12][C:8]2=[CH:9][S:10][CH:11]=[C:7]2[CH2:6]1)([OH:3])=[O:2]
Reactant: COC(=O)C1(SCc2ccc(OC)cc2)Cc2cscc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CSC2(C(=O)O)Cc3cscc3C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve 5-(carbomethoxy)-5-(4-methoxybenzylthio)-2,4,5,6-tetrahydro-cyclopenta[c]thiophene (1.14 g, 3.55 mmol) in 95% ethanol (25 mL), water (12 mL) and tetrahydrofuran (15 mL). Treat with potassium hydroxide (1.3 g, 23 mmol) and stir at room temperature for 1 hour. Filter and evaporate the solvent in vacuo. Partition between water (125 mL) and ether (75 mL). Separate theaqueous phase and acidify with cold concentrated hydrochloric acid. Extractwith methylene chloride (75 mL), dry (Na2SO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography to give 5-(carboxy)-5-(4-methoxybenzylthio)-2,4,5,6-tetrahydrocyclopenta[c]thiophene.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[S:7]1(=[O:24])=[O:23].[CH3:25][NH2:26]>CO>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:6]([CH2:5]/[CH:4]=[CH:3]/[CH2:2][NH:26][CH3:25])[S:7]1(=[O:24])=[O:23]
Reactant: O=S1(=O)N(C/C=C/CBr)c2ccccc2N1c1ccc(F)cc1F
Reactant: CN
Solvent: CO
Product: CNC/C=C/CN1c2ccccc2N(c2ccc(F)cc2F)S1(=O)=O

Procedure:
In an analogous manner to general procedure V, 1-[(2E)-4-bromobut-2-en-1-yl]-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.52 g, 1.2 mmol) was treated with 8N methylamine in methanol to give (2E)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbut-2-en-1-amine which was treated with 1N hydrochloric acid in ether to give its hydrochloride salt as a white solid (0.27 g, 54%). MS (ES) m/z 365.9 ([M+H]+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[NH:15][N:16]=[C:17]([O:18][C@@H:19]4[O:45][C@H:44]([CH2:46][O:47]C(=O)C(C)(C)C)[C@@H:36]([O:37]C(=O)C(C)(C)C)[C@H:28]([O:29]C(=O)C(C)(C)C)[C@H:20]4[O:21]C(=O)C(C)(C)C)[C:10]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].C(O)(=O)C>CO>[C@@H:19]1([O:18][C:17]2[C:10]3[C:11](=[N:12][CH:13]=[CH:14][C:9]=3[CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[NH:15][N:16]=2)[O:45][C@H:44]([CH2:46][OH:47])[C@@H:36]([OH:37])[C@H:28]([OH:29])[C@H:20]1[OH:21]
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3nccc(CCc4ccccc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: OC[C@H]1O[C@@H](Oc2n[nH]c3nccc(CCc4ccccc4)c23)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 50 °C
Reaction time: 5 h
Yield: 64.3 %

Procedure:
To a solution of 4-(2-phenylethyl)-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazolo-[3,4-b]pyridine (0.26 g) in methanol (5 mL) was added sodium methoxide (28% methanol solution, 0.067 mL), and the mixture was stirred at 50° C. for 5 hours. To the reaction mixture was added acetic acid (0.04 mL), and the resulting mixture was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1-5/1) to give the title compound (91 mg).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:24]1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.NC1C(C)=CC=CC=1>C(O)(=O)C>[C:17]1([C:16]2[C:10]3[N:9]=[CH:8][N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=4[CH3:24])[C:12](=[O:13])[C:11]=3[S:14][CH:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Solvent: CCOC(OCC)OCC
Solvent: Cc1ccccc1N
Solvent: CC(=O)O
Product: Cc1ccccc1-n1cnc2c(-c3ccccc3)csc2c1=O
Yield: 23 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (200 mg, 0.86 mmol), triethyl orthoformate (2 ml), o-toluidine (175 mg, 1.63 mmol), and acetic acid (0.2 ml) were used to give 62 mg (0.19 mmol, 23% yield) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[O:5][CH:6]=1.B(OC(C)C)(OC(C)C)OC(C)C.C([Li])CCC.CCCCCC.I[C:40]1[CH:45]=[C:44]([N+:46]([O-])=O)[CH:43]=[CH:42][C:41]=1[O:49][CH3:50].ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O.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]>[CH3:50][O:49][C:41]1[CH:42]=[CH:43][C:44]([NH2:46])=[CH:45][C:40]=1[C:2]1[CH:3]=[C:4]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[O:5][CH:6]=1
Reactant: CN1CCN(Cc2cc(Br)co2)CC1
Reactant: COc1ccc([N+](=O)[O-])cc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)OB(OC(C)C)OC(C)C
Solvent: O
Solvent: ClCCl
Solvent: CCCCCC
Product: COc1ccc(N)cc1-c1coc(CN2CCN(C)CC2)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 70.3 %

Procedure:
To a solution of 1-[(4-bromo-2-furyl)methyl]-4-methylpiperazine (1.43 g, 5.52 mmol) and tri-isopropyl borate (1.76 g, 9.38 mmol) in 20 mL of tetrahydrofuran at −78° C. was added 1.6 M n-butyl lithium in hexane (5.38 mL, 8.61 mmol) over 10 minutes. After stirring at −78° C. for 10 minutes, the temperature of the reaction mixture was allowed to rise to room temperature. Water (1.0 mL) was added and the solvents were removed in vacuo. The resultant intermediate boronic acid was dissolved in 20 mL of ethylene glycol dimethyl ether and 2-iodo-4-nitroanisole (1.06 mg, 4.25 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (87 mg, 0.11 mol) were added. A solution of 2.25 g of sodium carbonate in 6.5 mL of water was added and the resulting mixture was heated at reflux for 3 hours. The mixture was cooled to room temperature and partitioned between ethyl acetate and water. The aqueous layer was further extracted with ethyl acetate and the organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with a gradient of 5% methanol in dichloromethane to 10% methanol in dichloromethane to give 900 mg (70%) of (4-methoxy-3-{5-[(4-methylpiperazin-1-yl)methyl]-3-furyl}phenyl)amine as a red oil.
Reaction SMILES: [C:1]([CH:6]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:18])(OCC)=O.[C:19]1(=[O:23])[O:22]C[CH2:20]1.C1C=CC=CC=1.[H-].[Na+]>C(OCC)C.C1(C)C=CC=CC=1>[O:18]=[C:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:6]1[CH2:1][CH2:20][C:19]([OH:23])=[O:22]
Reactant: O=C1CCO1
Reactant: CCOC(=O)C1CCCCCCCCCCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(O)CCC1CCCCCCCCCCC1=O

Procedure:
The inventors have established a more effective method for producing β-(2-oxocyclododecyl)propionic acid by the following steps: reacting cyclododecanone with diethyl carbonate to give carbethoxycyclododecanone, reacting the carboethoxycyclododecanone with β-propiolactone in a solvent having no alkoxy group, such as benzene, toluene and ethyl ether in the presence of sodium hydride, hydrolyzing the resulting product, and then decarboxylating to give β-(2-oxocyclododecyl)propionic acid in high yield (79% based on the starting cyclododecanone theoretically).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12.[NH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([C:18]([NH2:20])=[O:19])[CH2:13]1.C(N(CC)C(C)C)(C)C>CN1C(=O)N(C)CC1.CCOC(C)=O.C(=O)([O-])O.[Na+]>[F:8][C:7]1[C:2]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([C:18]([NH2:20])=[O:19])[CH2:13]2)=[C:3]2[CH:11]=[CH:10][NH:9][C:4]2=[N:5][CH:6]=1
Reactant: Fc1cnc2[nH]ccc2c1Cl
Reactant: NC(=O)C1CCCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCN(C)C1=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)C1CCCN(c2c(F)cnc3[nH]ccc23)C1
Temperature: 200 °C
Yield: 10.8 %

Procedure:
A mixture of 4-chloro-5-fluoro-1H-pyrrolo[2,3-b]pyridine (30 mg), 3-piperidinecarboxamide (45 mg) and N,N-diisopropylethylamine (30 μL) in DMI (0.4 mL) was heated in the microwave reactor (200° C., 2 hours). The reaction mixture was allowed to cool to ambient temperature and diluted with EtOAc (10 mL) and half-saturated aqueous sodium hydrogencarbonate (10 mL). The aqueous phase was extracted with EtOAc (2×10 mL) and combined organic layers were washed with brine (20 mL), dried over MgSO4, and concentrated. Purification of the crude product by preparative silica gel thin-layer chromatography (EtOAc) gave 1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-3-piperidinecarboxamide (5 mg) as a pale brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]([CH3:18])=[N:16][CH:17]=2)N)=[CH:4][CH:3]=1.CO[CH:21](OC)[CH2:22][CH2:23][CH2:24][NH:25][CH3:26]>>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:8]([CH2:10][CH2:11][C:12]1[CH:13]=[N:14][C:15]([CH3:18])=[N:16][CH:17]=1)[CH:21]=[C:22]2[CH2:23][CH2:24][NH:25][CH3:26]
Reactant: Cc1ncc(CCN(N)c2ccc(Cl)cc2)cn1
Reactant: CNCCCC(OC)OC
Product: CNCCc1cn(CCc2cnc(C)nc2)c2ccc(Cl)cc12

Procedure:
The title compound is prepared by General Method 3 using 1-(4-chlorophenyl)-1-(2-(2-methylpyrimidin-5-yl)ethyl)hydrazine and 4,4-dimethoxy-N-methylbutan-1-amine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)[N:3]=1.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:8][C:6]1[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][N:14]([C:24]([C:23]4[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=4[C:18]4[S:17][CH:21]=[CH:20][CH:19]=4)=[O:25])[CH2:15]3)[CH2:10]2)[N:5]=1
Reactant: O=C(O)c1ccccc1-c1cccs1
Reactant: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
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: CN(C)C=O
Product: Cc1cc(C)nc(N2C[C@@H]3CCN(C(=O)c4ccccc4-c4cccs4)C[C@@H]32)n1
Yield: 58.9 %

Procedure:
A mixture of (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane (Intermediate 4, 28 mg, 0.13 mmol), 2-thiophen-2-yl-benzoic acid (29 mg, 0.14 mmol), HATU (73.2 mg, 0.19 mmol), diisopropylethylamine (50 mg, 0.38 mmol) was stirred in DMF (4 mL) at room temperature for 2 h. Then the reaction mixture was partitioned between water and ethyl acetate mixture. The organic phase was separated and washed with 1N aq. NaOH (10 mL) and then with water (2×15 mL). The organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified on HPLC (basic system) to yield the title compound (31.0 mg, 59.8%). MS (ESI) mass calcd. for C23H24N4OS, 404.53; m/z found, 405.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.60-6.75 (m, 7H), 6.43-6.10 (m, 1H), 4.10-1.78 (m, 16H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:7]([OH:19])[C:8](=[O:18])[NH:9][C@@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11].C(N(CC)CC)C.[N:35]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>O1CCOCC1>[OH:19][CH:7]([C@@H:6]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:41]([N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)=[O:42])[C:8](=[O:18])[NH:9][C@@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11]
Reactant: O=C(Cl)N1CCOCC1
Reactant: C[C@@H](NC(=O)C(O)[C@H](CCCCN)NC(=O)OC(C)(C)C)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C[C@@H](NC(=O)C(O)[C@H](CCCCNC(=O)N1CCOCC1)NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 78.9 %

Procedure:
To a slurry of 1.04 g (2.7 mmol) of tert-butyl (1S)-5-amino-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate and 0.38 mL (2.7 mmol) of trietylamine in 45 mL of dioxane was added 0.24 mL (2.7 mmol) of 4-morpholinecarbonyl chloride. The flask was heated with a heat gun until the mixture became homogeneous and was stirred at room temperature for 5 d. The reaction was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 6:4 acetone:hexanes to afford 1.05 g (78%) of tert-butyl (1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)-5-[(4-morpholinylcarbonyl)amino]pentylcarbamate. 1H NMR (400 MHz, DMSO-d6) δ 7.95 (m, 1H), 7.27 (m, 4H), 7.16 (m, 1H), 6.41 (m, 1H), 6.01 (d, J=9 Hz, 1H), 5.47 (d, J=6 Hz, 1H), 4.87 (qnt, J=7 Hz, 1H), 3.80 (dd, J=3 Hz, J=6 Hz, 1H), 3.65 (m, 1H), 3.46 (t, J=5 Hz, 4H), 3.16 (t, J=5 Hz, 4H), 2.93 (q, J=6 Hz, 2H), 1.13-1.44 (m, 18H). ES-LCMS m/z 493 (M+H).
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH2:22])[NH:20][N:21]=2)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1.[CH2:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:40]=[CH:39][C:34]([C:35](OC)=[O:36])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)[CH3:24].Cl>C1(C)C=CC=CC=1.CO>[CH3:14][O:13][C:11]1[CH:10]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH:22][C:35](=[O:36])[C:34]3[CH:33]=[CH:32][C:31]([N:28]4[CH2:27][CH2:26][N:25]([CH2:23][CH3:24])[CH2:30][CH2:29]4)=[CH:40][CH:39]=3)[NH:20][N:21]=2)[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=1
Reactant: CCN1CCN(c2ccc(C(=O)OC)cc2)CC1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: CCN1CCN(c2ccc(C(=O)Nc3cc(CCc4cc(OC)cc(OC)c4)n[nH]3)cc2)CC1
Temperature: 60 °C
Reaction time: 24 h
Yield: 51.3 %

Procedure:
Trimethylaluminium (2M in toluene, 1.51 mL, 3.02 mmol) was added dropwise to 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (299 mg, 1.21 mmol) and methyl 4-(4-ethylpiperazin-1-yl)benzoate (300 mg, 1.21 mmol) in toluene (6.0 mL) at 25° C. The resulting suspension was stirred at 60° C. for 24 h under nitrogen. The reaction mixture was added to methanol (100 mL) and was treated with HCl (2N aqueous solution, until the pH was 7 or lower). The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford impure product. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 5% 7M NH3/MeOH in DCM. Pure fractions were evaporated to dryness to afford the title compound (288 mg, 51%) as a cream solid.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:23]Cl>>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:23][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:2][CH2:3]1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Product: Nc1nc(N)c2c(N3CCN(Cc4ccc(Cl)c(Cl)c4)CC3)cccc2n1
Yield: 69 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 3,4-Dichlorobenzyl Chloride (72.3 mg; 0.37 mmol) to obtain 55.8 mg. (69% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 8.50 (s, 1H), 7.61 (m, 3H), 7.35 (dd, J=8.4, 1.4 Hz, 1H), 7.16 (m, 4H), 3.59 (s, 2H), 3.02 (br d, J=10.8 Hz, 3H), 2.90 (m, 3H), 2.31 (m, 2H). ESIMS+403.5 m/z
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([C@@H:12]3[CH2:15][C@H:14]([C:16]([NH2:18])=[O:17])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:19]1([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][C:29](B4OC(C)(C)C(C)(C)O4)=[CH:30][CH:31]=3)[N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>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.O>[NH2:1][C:2]1[C:3]2[C:10]([C:29]3[CH:28]=[C:27]4[C:32]([CH:33]=[CH:34][C:25]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)=[N:26]4)=[CH:31][CH:30]=3)=[CH:9][N:8]([C@@H:12]3[CH2:15][C@H:14]([C:16]([NH2:18])=[O:17])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Reactant: Nc1ncnc2c1c(I)cn2[C@H]1C[C@@H](C(N)=O)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2[C@H]1C[C@@H](C(N)=O)C1
Temperature: 80 °C

Procedure:
A mixture of cis-3-(4-amino-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutanecarboxylic acid amide (131 mg, 0.367 mmol), 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (146 mg, 0.441 mmol), Na2CO3 (97.2 mg, 0.917 mmol), Pd(PPh3)4 (25.5 mg, 0.0221 mmol), DMF (5 mL), and water (1 mL) was purged with nitrogen for 30 min and heated to 80° C. for 18 h. To the cooled reaction solution was added water (15 mL), the mixture was extracted with EtOAc (3×20 mL), the combined organic layers were washed with water (2×15 mL) and brine, dried over MgSO4, filtered, and concentrated. The residue was triturated with MeOH to give the title compound as yellow solid. 1H NMR (CDCl3, 400 MHz): δ=2.60-2.70 (m, 4H), 2.84-2.90 (m, 1H), 5.14-5.23 (quintet, 1H, J=8.7 Hz), 6.31 (brs, 2H), 6.92 (s, 1H), 7.40 (s, 1H), 7.50-7.62 (m, 3H), 7.78-7.82 (m, 2H), 8.08-8.10 (d, 1H, J=8.4 Hz), 8.15-8.23 (m, 3H), 8.30-8.37 (m, 2H), 8.49-8.51 (d, 1H, J=8.4 Hz). MS (ES+): 435.0 [MH+]. HPLC: tR=2.4 min (polar—5 min).