Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]2[CH:15]=[C:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=2)=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:3]=1.[C:31]([O:38][CH3:39])(=[O:37])[CH2:32][CH2:33][C:34]([O-])=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][CH2:10][CH2:11][N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:15]=2)[C:34](=[O:35])[CH2:33][CH2:32][C:31]([O:38][CH3:39])=[O:37])=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:3]=1
Reactant: COC(=O)CCC(=O)[O-]
Reactant: CCCCCNc1nc(N)nc(C)c1CCCNCc1cccc(CC(=O)OC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCCCCNc1nc(N)nc(C)c1CCCN(Cc1cccc(CC(=O)OC)c1)C(=O)CCC(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.1 %

Procedure:
The product from Example 1 (61 mg), mono-methyl succinate (23.4 mg) and TEA (0.062 ml) were dissolved in DCM (15 ml) then HATU (61.7 mg) was added. The resulting solution was stirred at rt for 16 h. The solvents were evaporated, the residue was taken up in MeOH and the crude product was purified by RPHPLC to afford the title compound as a colorless gum 32 mg.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:14]([C:18]1[N:22]([CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:21]2[CH:30]=[CH:31][C:32]([S:34]([N:37]3[CH:41]=[C:40]([C:42](O)=[O:43])[CH:39]=[N:38]3)(=[O:36])=[O:35])=[CH:33][C:20]=2[N:19]=1)([CH3:17])([CH3:16])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:14]([C:18]1[N:22]([CH2:23][CH:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[C:21]2[CH:30]=[CH:31][C:32]([S:34]([N:37]3[CH:41]=[C:40]([C:42]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:43])[CH:39]=[N:38]3)(=[O:36])=[O:35])=[CH:33][C:20]=2[N:19]=1)([CH3:15])([CH3:16])[CH3:17]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)O)cn3)ccc2n1CC1CCOCC1
Reactant: CC(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)c1cnn(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)c1
Yield: 70.2 %

Procedure:
Following the same procedure in Example 24, Step A, using iso-propylamine (9 mg, 0.15 mmol), DIPEA (28 uL, 21 mg, 0.16 mmol), 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrazole-4-carboxylic acid (0.073 mmol) and HATU (44 mg, 0.12 mmol) in DMF (2.5 mL). The crude product was purified by MPLC using Hex/EtOAc (1:2) on silica gel to give 25 mg (70%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.17 (d, J=6.45 Hz, 6 H), 1.40-1.56 (m, 4 H), 1.59 (s, 9 H), 2.18-2.40 (m, 1 H), 3.23-3.39 (m, 2 H), 3.81-3.96 (m, 2 H), 4.02-4.18 (m, 1 H), 4.41 (d, J=7.42 Hz, 2 H), 7.91 (d, J=8.8 Hz, 1 H), 7.98 (dd, J=8.8, 1.8 Hz, 1 H), 8.04 (s, 1 H), 8.33 (d, J=1.76 Hz, 1 H), 8.77 (d, J=0.78 Hz, 1 H); MS (ESI) (M+H)+=488.0; Anal. Calcd for C24H33N5O4S+0.70 TFA+0.50 EtOAc+0.40H2O (624.71): C, 53.64; H, 6.21; N, 11.21. Found: C, 53.58; H, 6.23; N, 11.28.
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[N:25]1([CH:31]2[CH2:37][CH2:36][C:35]3[CH:38]=[C:39]([NH2:42])[CH:40]=[CH:41][C:34]=3[CH2:33][CH2:32]2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:23][N:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:42][C:39]3[CH:40]=[CH:41][C:34]4[CH2:33][CH2:32][CH:31]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[CH2:37][CH2:36][C:35]=4[CH:38]=3)[N:24]=2)[CH:9]=[CH:8][CH:7]=1)[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CN(c1ccccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O
Reactant: Nc1ccc2c(c1)CCC(N1CCOCC1)CC2
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN(c1ccccc1CNc1cccn2nc(Nc3ccc4c(c3)CCC(N3CCOCC3)CC4)nc12)S(C)(=O)=O

Procedure:
N-Methyl-N-(2-{[2-(7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino]-methyl}-phenyl)-methanesulfonamide was prepared from N-{2-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-phenyl}-N-methyl-methanesulfonamide (100.0 mg, 0.2733 mmol) and 7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (75.0 mg, 0.304 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.019 g, 12%). MP=118-135° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 7.81 (d, J=6.8 Hz, 1H), 7.55-7.50 (m, 1H), 7.37-7.28 (m, 5H), 7.07 (d, J=7.8 Hz, 1H), 6.67 (t, J=7.0 Hz, 1H), 6.62 (s, 1H), 6.36 (d, J=7.4 Hz, 1H), 5.26-5.20 (m, 1H), 4.72 (d, J=5.1 Hz, 2H), 3.70 (br s, 4H), 3.31 (s, 3H), 3.01 (s, 3H), 2.91-2.50 (m, 9H), 2.15-2.00 (m, 2H), 1.53-1.35 (m, 2H). MS=576 (MH)+.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:9])([CH2:7][CH3:8])[C:4]([OH:6])=[O:5].[CH3:10]O>O1CCOCC1>[NH2:2][C:3]([CH3:9])([CH2:7][CH3:8])[C:4]([O:6][CH3:10])=[O:5]
Reactant: CO
Reactant: CCC(C)(N)C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: CCC(C)(N)C(=O)OC
Temperature: 50 °C

Procedure:
2-amino-2-methylbutanoic acid HCl salt (20 g, 130.2 mmol) was suspended in 150 mL methanol. A solution of HCL (4M in dioxane was added and the mixture heated to 50° C. overnight. The mixture was cooled to room temperature and evaporated to dryness under vacuum. The resulting isovaline methyl ester (20 g) was used without further purification. 1H NMR (300 MHz, DMSO) δ 3.78-3.64 (m, 1H), 3.61 (s, 3H), 3.54-3.41 (m, 1H), 2.50 (d, J=1.6 Hz, 1H), 1.76 (s, 2H), 1.66-1.35 (m, 2H), 1.17 (s, 3H), 0.77 (t, J=7.5 Hz, 3H).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[C:9]([OH:10])=[C:8]([CH3:11])[CH:7]=[CH:6][N:5]=1>N1C=CC=CC=1>[Br:1][C:6]1[N:5]=[C:4]([CH3:3])[C:9]([OH:10])=[C:8]([CH3:11])[CH:7]=1
Reactant: Cc1ccnc(C)c1O
Reactant: BrBr
Solvent: c1ccncc1
Product: Cc1cc(Br)nc(C)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
A solution of bromine (4.2 mL, 81.2 mmol) in anhydrous pyridine (80 mL) was added dropwise to a solution of 2,4-dimethyl-3-hydroxypyridine (10.0 g, 81.2 mmol) in anhydrous pyridine (160 mL). The mixture was stirred at room temperature for 1 hour, concentrated under reduced pressure and then further dried under vacuum. The residue was taken up in water (100 mL) and the resulting mixture was stirred for 0.5 hour at room temperature. The precipitated solid was collected by filtration, washed with water and air dried overnight to afford 8.7 g (53%) of the title compound.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][CH2:11][OH:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1.O>CN(C)C=O>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([O:12][CH2:11][CH2:10][CH2:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[N:15][CH:16]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(F)nc1
Reactant: OCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCCCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
Sodium hydride (99 mg, 4.14 mmol) was added to a solution of 3-phenyl-1-propanol (564 μL, 4.14 mmol) in N,N-dimethylformamide (15 mL) while cooling in ice, and the mixture was stirred for 30 min while cooling in ice. A solution of 2-fluoro-5-nitropyridine (500 mg, 3.45 mmol) in N,N-dimethylformamide (5 mL) was added thereto. The mixture was warmed to room temperature and stirred for 19 hr. Subsequently, sodium hydride (99 mg, 4.14 mmol) was added thereto and the mixture was stirred at room temperature for 2 hr. Thereafter, the mixture was heated to 85° C., stirred for 1.5 hr, and further stirred at room temperature for 2 hr. Water was added to the reaction mixture while cooling in ice, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1 mol/L hydrochloric acid and dried over anhydrous magnesium sulfate. The desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1) to afford 5-nitro-2-(3-phenylpropoxy)pyridine as a brown solid (440 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:20])=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:19])[CH:5]=[CH:6][CH:7]=1.[C:21]([O-])([O-])=O.[Cs+].[Cs+].IC>CN(C=O)C>[Br:1][C:2]1[C:3]([CH3:20])=[C:4]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:21])[C:9]2=[O:19])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1c(Br)cccc1-n1c(=O)[nH]c2ccccc2c1=O
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1c(Br)cccc1-n1c(=O)c2ccccc2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
A suspension of 3-(3-bromo-2-methylphenyl)quinazoline-2,4(1H,3H)-dione (23.02 g, 69.5 mmol) and Cs2CO3 (34.0 g, 104 mmol) in DMF (70 mL) cooled in an ice-water bath was treated portionwise with iodomethane (5.22 mL, 83 mmol). The mixture was warmed to room temperature and stirred for 30 min. The mixture was filtered and the filtrate was concentrated. The residue was partitioned between EtOAc and water. A precipitate which formed was collected by filtration. The collected solid was washed with water and dried overnight under vacuum to give a white solid. The organic phase of the filtrate was separated, washed 3 times with 10% aqueous LiCl, then was washed twice with water, dried and concentrated to give additional solid. The two solids were combined to give 3-(3-bromo-2-methylphenyl)-1-methylquinazoline-2,4(1H,3H)-dione as a white solid (15.56 g, 92% yield). Mass spectrum m/z 345, 347 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:11]1([C:16]2[S:20][C:19]([NH2:21])=[N:18][N:17]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl>[CH:11]1([C:16]2[S:20][C:19]([NH:21][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])=[N:18][N:17]=2)[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=C(O)c1ccccc1F
Reactant: Nc1nnc(C2CCCC2)s1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(Nc1nnc(C2CCCC2)s1)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
To a 20 ml scintillation vial was added 2-fluorobenzoic acid (845 mg, 5.0 mmol) and commercially available 5-cyclopentyl-1,3,4-thiadiazol-2-amine (intermediate 49) (700 mg, 5.0 mmol). To this was added EDC (960 mg, 5 0 mmol) and HOAt (675 mg, 5.0 mmol) followed by 25 ml DCM. The reaction mixture was stirred with a Teflon covered magnetic stir-bar at room temperature for overnight. The product was collected by ethyl acetate and 5% HCl solution work up, and then to purified by column (CH3OH/DCM, 1-10% gradient system), yielding N-(5-cyclopentyl-1,3,4-thiadiazol-2-yl)-2-fluorobenzamide (0.61 g, 42%) as solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[N:25]4[C:19]([CH2:20][NH:21][CH2:22][C:23]5[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:24]=54)=[N:18][N:17]=3)[CH2:12][CH2:11]2)=[N:2]1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[N:25]4[C:19]([CH2:20][N:21]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:22][C:23]5[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:24]=54)=[N:18][N:17]=3)[CH2:12][CH2:11]2)=[N:2]1
Reactant: CS(=O)(=O)Cl
Reactant: Clc1ccc2c(c1)CNCc1nnc([C@H]3CC[C@H](c4nsc5ccccc54)CC3)n1-2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](c3nsc4ccccc43)CC2)C1
Reaction time: 20 h

Procedure:
To a solution of trans-1-(4-benzo[d]isothiazol-3-yl-cyclohexyl)-8-chloro-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (35 mg, 0.080 mmol) and triethylamine (0.022 ml, 0.16 mmol) in dichloromethane (0.8 ml) was added methanesulfonyl chloride (0.013 ml, 0.16 mmol) at room temperature. Stirring for 20 h was followed by quenching with methanol (0.5 ml). The mixture was concentrated in vacuo. Preparative RP-HPLC with water (0.05% formic acid)/methanol as eluent gave the title compound (34 mg, 82%) as white solid: MS m/e: 514 ([M+H]+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([CH3:14])=[N:10]2)=[C:5]2[NH:15][CH:16]=[C:17]([C:18](=[O:22])[C:19]([OH:21])=O)[C:4]=12.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[CH2:31][CH2:32][NH:33][CH2:34]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([CH3:14])=[N:10]2)=[C:5]2[NH:15][CH:16]=[C:17]([C:18](=[O:22])[C:19]([N:33]3[CH2:32][CH2:31][C:30]4[C:35](=[CH:36][CH:37]=[N:38][C:29]=4[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=4)[CH2:34]3)=[O:21])[C:4]=12
Reactant: c1ccc(-c2nccc3c2CCNC3)nc1
Reactant: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)O)c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)N3CCc4c(ccnc4-c4ccccn4)C3)c12
Temperature: 25 °C
Reaction time: 15.75 h

Procedure:
To a suspension of 2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (0.062 g, 0.205 mmol), 5-(pyridin-2-yl)-1,2,3,4-tetrahydro-2,6-naphthyridine (0.062 g, 0.205 mmol), and TBTU (0.086 g, 0.267 mmol) in DMF (3 mL) was added Hunig's Base (0.2 mL, 1.145 mmol). The mixture was stirred at rt for 15.75 h and quenched with 5 mL of water and concentrated under reduced pressure. The residue was dissolved in DMF, filtered through a plug of glass wool, and was purified by prep HPLC. The fractions containing the expected product were combined and concentrated. The residue was dissolved in dichloromethane and washed with sat. aq. NaHCO3. The organic layer was dried with MgSO4, was filtered, and was concentrated under reduced pressure to give the expected product as a light pink solid. The compound was further purified using BIOTAGE® flash chromatography with a 0-6% MeOH in dichloromethane gradient. The expected product, 1-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(5-(pyridin-2-yl)-3,4-dihydro-2,6-naphthyridin-2(1H)-yl)ethane-1,2-dione, 1.4 H2O (0.041 g, 0.077 mmol, 37.7% yield), was isolated as an off-white solid. LC/MS: m/z 495.19 (M+H)+, 0.922 min (method 4). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.04 (br. s., 1H) 9.07-9.12 (m, 1H) 8.48-8.71 (m, 2H) 8.20-8.26 (m, 1H) 7.79-7.90 (m, 2H) 7.71-7.74 (m, 1H) 7.27-7.37 (m, 1H) 7.00-7.23 (m, 1H) 4.80-5.00 (m, 2H) 3.75-3.96 (m, 5H) 3.22-3.36 (m, 2H) 2.50-2.61 (m, 3H) 1.57 (s, 3H).
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:14][C:13](=S)[CH2:12][CH2:11][CH:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:9]=2[CH:23]=1>O1CCCC1>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:14][CH:13]([NH:2][NH2:3])[CH2:12][CH2:11][CH:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:9]=2[CH:23]=1
Reactant: Fc1ccccc1C1CCC(=S)Nc2ccc(Cl)cc21
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Product: NNC1CCC(c2ccccc2F)c2cc(Cl)ccc2N1
Reaction time: 2 h

Procedure:
A solution of 17.5 ml of hydrazine hydrate in 1.75 l of tetrahydrofuran is treated with 22 g of 7-chloro-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1-benzazepine-2-thione. The solution is stirred under a stream of argon for 2 hours and then evaporated at 40° in vacuo. The residue is crystallized from ether and there is obtained 7-chloro-5-(2-fluorophenyl)-2-hydrazino-4,5-dihydro-2H-1-benzazepine of melting point 213°-215°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]1=2.[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.O.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>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)=[CH:26][CH:25]=1
Reactant: Cc1ccc2c(c1)c1c(n2-c2ccccc2Br)CCN(C)C1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2-c2ccccc2-c2ccc(F)cc2)CCN(C)C1
Temperature: 95 °C
Yield: 18.4 %

Procedure:
To a de-aerated solution of 5-(2-bromo-phenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.282 mmol), 4-fluorophenylboronic acid (59 mg, 0.423 mmol) and K3PO4 (149 mg, 0.706 mmol) in DMF-water (4:1 mL) was added PdCl2(PPh3)2 (10 mg, 5 mol %). The reaction mixture was heated at 95° C. for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield crude, which was purified by reverse phase HPLC to yield 5-(4′-fluoro-biphenyl-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as semisolid (19.23 mg). 1H NMR (Oxalate salt, CD3OD) δ (ppm): 7.65-7.59 (m, 3H), 7.41 (d, 1H), 7.25 (s, 1H), 7.15 (m, 1H), 7.05-6.85 (m, 5H), 4.5-3.39 (m, 2H), 3.6-3.5 (m, 1H), 3.2-3.19 (m, 1H), 2.95 (s, 3H), 2.85-2.8 (m, 1H), 2.59-2.50 (m, 1H), 2.4 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH3:23][NH2:24]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14]([NH:24][CH3:23])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Reactant: CN
Solvent: CN(C)C=O
Product: CNc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A quantity of 0.165 g (0.47 mmol) of 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 37 was placed in a pressure tube with a magnetic stirring bar. The tube was cooled in a dry ice-acetone bath and ca. 3 mL of monomethylamine gas was condensed in the tube. Dimethylformamide (1.0 mL) was added, and the tube was closed and allowed to warm to room temperature. With stirring, the reaction mixture was heated behind a shield in a 110° C. oil bath. After 10 minutes, all solid was in solution. The solution was heated in the oil bath for 20 hours. The tube was cooled in an ice-acetone bath, opened, and warmed to room temperature to vent the excess amine. Most of the dimethylformamide was evaporated at reduced pressure to yield crystals. The solid was triturated with 5 mL of water, filtered, washed with water and dried; wt 0.128 g. Purification was effected by recrystallization from ethyl acetate-petroleum ether to give 0.081 g of pure product; mp 243°-244° C.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[N:26]1[CH2:33][CH:32]2[NH:34][CH2:35][CH:27]1[CH2:28][CH:29]=[CH:30][CH2:31]2.CCN(C(C)C)C(C)C>C(O)C>[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[N:26]1[CH2:33][CH:32]2[N:34]([CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]3[CH:15]=[CH:14][CH:13]=[C:12]4[C:7]=3[CH:8]=[CH:9][CH:10]=[N:11]4)[CH2:35][CH:27]1[CH2:28][CH:29]=[CH:30][CH2:31]2
Reactant: C1=CCC2CNC(C1)CN2c1ccc2ccccc2c1
Reactant: c1cc(OCC2CO2)c2cccnc2c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: OC(COc1cccc2ncccc12)CN1CC2CC=CCC1CN2c1ccc2ccccc2c1

Procedure:
5-Oxiranylmethoxy-quinoline (13 mg, 0.065 mmol), 7-naphthalen-2-yl-7,9-diaza-bicyclo[4.2.2]dec-3-ene (20 mg, 0.042 mmol), DIPEA (0.1 mL, 0.55 mmol) and ethanol (2 mL) were μW for 900 sec at 130° C. in a μW reaction tube. The solvent was evaporated in vacuo to yield a crude solid that was purified with flash chromatography gradient [30% EtOAc/heptane to 100% EtOAc] to yield the title compound as its free base, as a residue.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:18])[C@@H:12]2[C@@H:15]([OH:17])[CH3:16])[C:9]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])(=[O:3])[CH3:2].Cl[Si:33]([CH3:36])([CH3:35])[CH3:34]>N1C=CC=CC=1>[C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:18])[C@@H:12]2[C@@H:15]([O:17][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH3:16])[C:9]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@H](C)O)[C@H]2C1
Reactant: C[Si](C)(C)Cl
Solvent: c1ccncc1
Product: CC(=O)NCCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@H](C)O[Si](C)(C)C)[C@H]2C1

Procedure:
p-Nitrobenzyl (5R,6S)-3-(2-acetamidoethylthio)-6-[(1S)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (250 mg) in pyridine (7 ml) were treated with 70 mg. aliquots of chlorotrimethylsilane until all the starting hydroxycompound has reacted (4 aliquots required). The pyridine was removed by evaporation in vacuo, ethyl acetate (20 ml) was added to the residue and the resultant solution washed with water (20 ml). The ethyl acetate was dried (MgSO4) and evaporated in vacuo. Toluene (20 ml) was added to the residue and evaporated in vacuo to remove residual traces of pyridine. The crude silyl ether was then chromatographed on silica gel (0.040-0.063 mm; 15 g) eluting with ethyl acetate. Fractions containing the trimethylsilyl ether were combined and evaporated in vacuo to yield p-nitrobenzyl (5R, 6S)-3-(2-acetamidoethylthio)-6-[(1S)-1-trimethylsilyloxyethyl]7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (145 mg). Found M+ m/e 521.1657 C23H31N3O7SSi requires m/e 521.1650.
Reaction SMILES: [CH:1]1([CH2:4][S:5]([CH2:8][C@H:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])[C:10]([OH:12])=O)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C1(N=C=N)CCCCC1.OC1C2N=NNC=2C=CC=1.[NH2:41][CH:42]1[CH:47]([OH:48])[CH2:46][CH2:45][CH2:44][CH:43]1[OH:49].C(O)C(N)(CO)CO>C(Cl)Cl>[CH:1]1([CH2:4][S:5]([CH2:8][C@H:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])[C:10](=[O:12])[NH:41][CH:42]2[CH:47]([OH:48])[CH2:46][CH2:45][CH2:44][CH:43]2[OH:49])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: O=C(O)[C@H](CS(=O)(=O)CC1CC1)NC(=O)N1CCOCC1
Reactant: NC1C(O)CCCC1O
Agent: N=C=NC1CCCCC1
Agent: NC(CO)(CO)CO
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: O=C(NC1C(O)CCCC1O)[C@H](CS(=O)(=O)CC1CC1)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73.8 %

Procedure:
A mixture of (R)-3-cyclopropylmethanesulfonyl-2-[(morpholine-4-carbonyl)-amino]-propionic acid (0.352 g, 1.1 mmol) and N-cyclohexylcarbodiimide N′-methylpolystyrene (1.93 mmol/g, 1.03 g) in DCM (10 mL) was treated with hydroxybenzotriazole (0.27 g, 2 mmol). After stirring at room temperature for 5 minutes the mixture was treated with 2-amino-cyclohexane-1,3-diol (0.0.13 g, 1 mmol) and stirring was continued for a further 2 days. The reaction mixture was treated with PS Trisamine (3.75 mmol/g, 1.3 g) and after stirring at room temperature for 2 hours the resin was filtered off and washed with DCM. The combined filtrate plus washings were evaporated under reduced pressure to give morpholine-4-carboxylic acid [(R)-2-cyclopropylmethanesulfonyl-1-(2,6-dihydroxy-cyclohexylcarbamoyl)-ethyl]-amide (0.32 g) as pale yellow thick oil. MS: 434 (MH+).