Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=O.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.P(Cl)(Cl)Cl>O>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][C:13]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=3)=[O:15])=[CH:19][CH:18]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: Cc1ccc2c(O)c(C(=O)O)cnc2n1
Solvent: ClP(Cl)Cl
Solvent: O
Product: Cc1ccc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc2n1
Reaction time: 3 h
Yield: 5 %

Procedure:
A solution of 4-hydroxy-7-methyl[1,8]naphthyridine-3-carboxylic acid (0.204 g) and 4-chlorobenzylamine (0.12 mL) is heated to reflux. To this is added dropwise phosphorus trichloride (0.04 mL). Refluxing is continued for 3 h. The mixture is cooled and water is added to destroy excess PCl3. The solvents are removed. The residue is partitioned between EtOAc and water. The aqueous layer is extracted with EtOAc (3×). The combined organic layers are washed with brine (1×), dried and condensed. The residue is adsorbed on silica and chromatographed (eluent 5% MeOH/CH2Cl2). Fractions homogeneous by TLC are condensed and triturated with Et2O/hexanes to yield 0.017 g (5%) of the desired product as a yellow solid. Physical characteristics are as follows: m.p. 280-285° C. (dec); 1H NMR (300 MHz, DMSO) δ 13.0, 10.20, 8.63, 8.47, 7.38, 4.52, 2.61; IR (mull) 3186, 3148, 3055, 3034, 1655, 1605, 1570, 1546, 1494, 1333, 1243, 1097, 814, 799, 623 cm−1; MS (EI) m/z 327 (M+), 188, 187, 161, 160, 142, 140, 132, 131, 104; HRMS (EI) calcd for C17H14ClN3O2 327.0775, found 327.0783.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[S:18](Cl)(=[O:20])=[O:19]>N1C=CC=CC=1>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][S:18]([C:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=2[CH3:10])(=[O:20])=[O:19])[C:3]([Cl:9])=[N:4][CH:5]=1
Reactant: Nc1cc(Br)cnc1Cl
Reactant: Cc1ccc(C)c(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Product: Cc1ccc(C)c(S(=O)(=O)Nc2cc(Br)cnc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
3-Amino-5-bromo-2-chloropyridine (510 mg) in dry pyridine (7 ml) was treated with 2,5-dimethylbenzenesulfonyl chloride (962 mg) then stirred at RT overnight. The reaction was purified by prep-HPLC. The combined fractions were concentrated to give a slurry, then filtered, rising with water and dried overnight to give title compound (441 mg).
Reaction SMILES: [C:1]([CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C:22]2[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=2)[C:13](=O)[C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[N:16][CH:15]=2)[CH2:8][CH2:7]1)[CH3:5])#[N:2].B.C1COCC1>C1COCC1>[NH2:2][CH2:1][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[CH3:20])[C:22]2[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=2)[CH2:8][CH2:7]1)[CH3:5]
Reactant: Cc1ccncc1C(=O)N(c1ccc(C(F)(F)F)nc1)C1CCN([C@H](C)CC#N)CC1
Agent: B
Solvent: C1CCOC1
Product: Cc1ccncc1CN(c1ccc(C(F)(F)F)nc1)C1CCN([C@H](C)CCN)CC1
Temperature: 65 °C
Yield: 58.5 %

Procedure:
To a solution of (R)-N-[1-(2-cyano-1-methyl-ethyl)-piperidin-4-yl]-4-methyl-N-(6-trifluoromethyl-pyridin-3-yl)-nicotinamide (0.62 g, 1.44 mmol) in THF (25 mL) was added a solution of borane-THF in THF (1.0 M, 8.62 mL, 8.62 mmol) and the reaction was refluxed for 16 h. The reaction was cooled and carefully quenched with 9N HCl (14 mL) and heated to 65° C. for 2 h. The mixture was cooled and concentrated to remove the THF. The remaining aqueous solution was neutralized to pH>13 with 10N NaOH and diluted with CH2Cl2 (50 mL). The two phases were separated and the aqueous layer was extracted with CH2Cl2 (4×50 mL). The combined organic extracts were dried (Na2SO4) and purified by column chromatography on silica gel (92:7:1, CH2Cl2/MeOH/NH4OH) to afford [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-methyl-pyridin-3-ylmethyl)-(6-trifluoromethyl-pyridin-3-yl)-amine as a pale yellow oil (0.355 g, 58%). 1H-NMR (CDCl3) δ 0.98 (d, 3H, J=7 Hz), 1.41 (m, 2H), 1.51 (m, 2H), 1.68 (m, 4H), 1.91 (m, 2H), 2.72 (dt, 1H, J=2 Hz, 12 Hz), 2.35 (s, 3H), 2.51 (dt, 1H, J=2 Hz, 11 Hz), 2.72 (m, 3H), 2.86 (m, 2H), 3.84 (m, 1H), 4.46 (s, 2H), 6.90 (dd, 1H, J=3 Hz, 9 Hz), 7.11 (d, 1H, J=5 Hz), 7.42 (d, 1H, J=9 Hz), 8.08 (d, 1H, J=3 Hz), 8.24 (s, 1H), 8.39 (d, 1H, J=5 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:5]2.[H-].[Na+].[CH3:21]I.[Cl-].[NH4+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:21])[C:6]([C:11](=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:5]2
Reactant: CCCCCCC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCCCCC(=O)c1cc2cc(Cl)ccc2n1C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To a solution (10 mL) of 1-(5-chloro-1H-indol-2-yl)heptan-1-one (1.00 g) synthesized in Example A106(2) in N,N-dimethylformamide was added sodium hydride (60%, oily, 182 mg) at 0° C. and the mixture was stirred under argon atmosphere for 30 min. After stirring, methyl iodide (354 μL) was added. The reaction mixture was stirred at room temperature overnight, saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with hexane to give the title object compound (367 mg, 35%) as a pale-brown solid.
Reaction SMILES: C([O:3][C:4](=[O:38])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Li+].C(O)C.Cl>O>[CH3:37][O:36][C:33]1[CH:32]=[CH:31][C:30]([C:27]2[CH:26]=[CH:25][C:24]([C:20]3[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]4[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:38])=[O:3])=[CH:14][CH:13]=4)[N:19]=3)=[CH:29][CH:28]=2)=[CH:35][CH:34]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccc(OC)cc4)cc3)oc2C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2ccc(-c3nc(CCOc4ccc(OC(C)(C)C(=O)O)cc4)c(C)o3)cc2)cc1

Procedure:
To a 20 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4′-methoxybiphenyl-4-yl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (0.268 mmoles), lithium hydroxide (0.535 mmoles, 0.268 mL of a 2N solution), and ethanol (5 mL). This solution was heated to reflux for 2 h. Distilled water was added to the mixture and the pH was adjusted to 3 using a 1N HCl solution. The organic layer was extracted with ethyl acetate, washed with brine, and concentrated in-vacuo. This crude oil was re-solvated in pure ethyl acetate and filtered over a pad of Celite. The filtrate was concentrated in-vacuo, and the crude oil was crystallized using acetonitrile. The crystals were collected and dried in-vacuo affording 2-(4-{2-[2-(4′-methoxybiphenyl-4-yl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid. 1H NMR (400 MHz, CDCl3) 8.02 (2H, m), 7.64 (4H, m), 7.01(2H, m), 6.97 (2H, m), 6.91 (2H, m), 6.79 (2H, d), 4.20 (2H, t), 3.86 (3H, s), 3.00 (2H, t) 2.39 (3H, s), 1.52 (6H, s).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1)[CH3:5].O.[OH-].[Li+].Cl>CO.O>[OH:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:14][CH:15]=1)[CH3:5]
Reactant: COC(=O)c1ccc(C(C)CCO)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(CCO)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.8 %

Procedure:
To the solution of methyl 4-(4-hydroxybutan-2-yl)benzoate (354 mg, 1.7 mmol) in methanol (30 mL) and water (5 mL) was added lithium hydroxide hydrate (150 mg, 3.6 mmol) were added. The mixture was stirred at room temperature for 12 hours. Then the reaction mixture was acidified by hydrochloric acid aqueous solution (1N) to adjust pH=6 and extracted with dichloromethane (10 mL×3). The organic layers were combined and concentrated to give 4-(4-hydroxybutan-2-yl)benzoic acid (290 mg, 88%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Br:17][CH2:18][C:19](Br)=[O:20].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:19](=[O:20])[CH2:18][Br:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C(Br)CBr
Reactant: CC(=O)Oc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)Oc1ccc(-c2ccc(C(=O)CBr)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 50 g (236 mmol) of [1,1′-biphenyl]-4-yl acetate in 500 ml dichloromethane was placed under argon and cooled to 0° C. Bromoacetyl bromide (31.6 ml, 363 mmol) was added, followed by aluminium chloride (94.3 g, 707 mmol) which was added in portions under vigorous stirring over 30 min. The resulting mixture was stirred at 0° C. for a further 30 min and at room temperature overnight. The mixture was then slowly poured into 500 ml of cold 10% HCl and extracted three times with dichloromethane. The organic layer was dried over Na2SO4, filtered and evaporated. The residue was triturated with 1:1 diisopropyl ether/isopropanol, filtered, and the remaining solid dried under vacuum.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]([O:11][C:12](=[O:21])[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])[CH3:10].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][Br:28].[NH4+].[Cl-]>C1COCC1.CN1C(=O)N(C)CCC1>[Br:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][C:13]([CH3:14])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:12]([O:11][CH2:9][CH3:10])=[O:21]
Reactant: CCOC(=O)C(C)c1ccccc1
Reactant: BrCCCCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(CCCCCBr)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
Under N2 atmosphere, a solution of LDA (2.0 M in heptane/THF/ethylbenzene, 1.85 mL, 3.70 mol) was added dropwise to a stirred solution of 202 (660 g, 3.70 mol) in anhydrous THF (6.6 L) over 30 min at −78° C. After 1 h, 1,5-dibromopentane (1390 g, 6.05 mol) was added, followed by the addition of DMPU (660 mL). The reaction mixture was stirred for 1 h, then warmed to room temperature and stirred overnight. The mixture was poured into saturated aqueous NH4Cl solution (24 L) and extracted with ethyl acetate (4×6.7 L). The combined organic layers were washed with brine (9 L), 1 N HCl (6 L), saturated aqueous NaHCO3 solution (6 L), and brine (6 L). The solution was dried over MgSO4 and concentrated in vacuo. The residue was distilled in high vacuo to yield 205h (700g, 58%) as a yellowish oil. Bp 140-145° C./0.3 mmHg. 1H NMR (CDCl3): δ 7.30-7.20 (m, 5 H), 4.09 (m, 2 H), 3.34 (t, 2 H, J=6.9), 2.05-1.80 (m, 4 H), 1.53 (s, 3 H), 1.43-1.14 (m, 4 H), 1.16 (t, 3 H, J=6.6). 13C NMR (CDCl3): δ 176.03, 143.99, 128.33, 126.60, 125.89, 60.68, 50.11, 39.03, 33.75, 32.51, 28.59, 23.93, 22.78, 14.10. HRMS (LSIMS, nba): Calcd for C16H24BrO2 (MH+): 327.0960, found: 327.0952. HPLC: 91.2% pure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl[C:12]1[CH:22]=[C:16]2[N:17]([CH3:21])[CH2:18][CH2:19][CH2:20][N:15]2[C:14](=[O:23])[N:13]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[CH2:9][O:10][C:12]1[CH:22]=[C:16]2[N:17]([CH3:21])[CH2:18][CH2:19][CH2:20][N:15]2[C:14](=[O:23])[N:13]=1
Reactant: OCc1cc(F)cc(F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1cc(F)cc(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (3,5-difluorophenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [CH:1]12[S:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][C:3](=O)[CH2:2]2.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:31]=1)[NH:28][CH:27]=[CH:26]2.C([SiH](CC)CC)C>ClCCl>[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:31]=1)[NH:28][CH:27]=[C:26]2[CH:3]1[CH2:4][CH:5]2[S:8][CH:1]([CH2:7][CH2:6]2)[CH2:2]1
Reactant: CCOC(=O)c1cc(Br)cc2cc[nH]c12
Reactant: O=C1CC2CCC(C1)S2
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc(Br)cc2c(C3CC4CCC(C3)S4)c[nH]c12
Temperature: 23 °C
Reaction time: 8 h

Procedure:
To a solution of 8-thiabicyclo[3.2.1]octan-3-one (1.33 g, 9.32 mmol, 1 eq) in dry dichloromethane (50 mL) was added a spatula tip full of activated 4 A molecular sieves (beads). The ketone solution was cooled to 0° C., and trimethylsilyl triflate (1.7 mL, 9.41 mmol, 1 eq) was added dropwise followed by a solution of ethyl 5-bromo-1H-indole-7-carboxylate (2.5 g, 9.32 mmol, 1 eq) in dichloromethane (25 mL). The mixture was stirred at 23° C. overnight, then was cooled to 23° C. and triethylsilane (2.3 mL, 14.4 mmol, 1.5 eq) was added in a single portion. The reaction was stirred at 23° C. for 1.5 h, then quenched by the addition of saturated aqueous sodium bicarbonate. The mixture was extracted with dichloromethane, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by Isco Combiflash, 120 gram column, eluting with 0-30% ethyl acetate in hexanes. The ethyl 5-bromo-3-(8-thiabicyclo[3.2.1]oct-3-yl)-1H-indole-7-carboxylate was obtained as a mixture of isomers (2.38 g, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:28])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:31][NH:32][CH2:33][CH:34]([C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1)[OH:35].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:28])[C:12]3[S:19][C:18]([CH2:20][N:32]([CH2:33][CH:34]([OH:35])[C:36]4[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=4)[CH3:31])=[C:17]([CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:29][CH:30]=1
Reactant: CNCC(O)c1cccnc1
Reactant: COCCOCc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCc1c(CN(C)CC(O)c2cccnc2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 50 °C
Yield: 92.5 %

Procedure:
A mixture of 111 mg of N-(4-chlorobenzyl)-2-(chloromethyl)-3-[(2-methoxyethoxy)methyl]-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide, 54 mg of 2-(methylamino)-1-pyridin-3-ylethanol (Arch. Pharm. (1961), 294, 453), and 62 μL of diisopropylethylamine in 1.5 mL of DMF is heated at 50° C. for 18 h, then cooled and partitioned between EtOAc and water. The organic phase is washed with two additional portions of water and brine, dried (Na2SO4), and concentrated under reduced pressure. Flash chromatography of the residue on silica using 5% MeOH in CH2Cl2 affords 128 mg of the title compound as a white foam. Recrystallization of a sample from EtOAc provides white crystals.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.C[N:18](C=O)C>C(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:18])=[O:6]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cccc(I)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)c1cccc(I)c1
Yield: 90 %

Procedure:
3-Iodo-benzamide was prepared using a modification of the procedure by Remsen. (Remsen; Reid Am. Chem. J. 1899, 21, 289.) 3-Iodo-benzoic acid (28.68 g, 116 mmol) was stirred in CH2Cl2 (200 mL) at 23° C. under argon. Oxalyl chloride (30.2 mL, 349 mmol) was added slowly, and slow gas evolution was observed. DMF (0.1 mL) was then added, accelerated gas evolution considerably, and the reaction was stirred for. 2 h. Solvent was removed, and the brown oily residue was dissolved in THF (50 mL) and added to a solution of 18% aqueous NH4OH (260 mL) at 0° C. After stirring the mixture for 15 min, the liquid was decanted off, and the remaining sludge was acidified with 1 N HCl. The white solid was collected by filtration, washed with water, and dried under vacuum to give 25.68 g (90%) of 3-iodo-benzamide compound 32. 1H NMR (DMSO-d6) δ 8.21 (1 H, t, J=1.5 Hz), 8.05 (1 H, s), 7.87 (2 H, dd, J=8.1, 1.5 Hz), 7.47 (1 H, s), 7.25 (1 H, t, J=7.8 Hz); IR (KBr) 3343, 3164, 1661, 1628, 1561, 1424, 1389, 1125. Anal. (C7H6INO) C, H, N.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:49])[C@@H:9]([CH3:48])[C:10]([NH:12][C@@H:13]([CH:45]([CH3:47])[CH3:46])[C:14]([N:16]1[CH2:21][CH2:20][N:19](C(OCC2C=CC=CC=2)=O)[CH2:18][C@H:17]1[C:32]([NH:34][C@H:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38][CH2:37][CH2:36]1)=[O:33])=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[CH3:49][N:8]([C@@H:9]([CH3:48])[C:10]([NH:12][C@H:13]([C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][C@H:17]1[C:32]([NH:34][C@H:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38][CH2:37][CH2:36]1)=[O:33])=[O:15])[CH:45]([CH3:47])[CH3:46])=[O:11])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCN(C(=O)OCc2ccccc2)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCNC[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Reaction time: 2 h

Procedure:
Compound 6 (13.02 g, 19.2 mmol) is dissolved in MeOH (600 mL), to which is added 5% Pd/C (1.80 g). This mixture is stirred in a pressure vessel under an atmosphere of hydrogen (40 psi) for 2 h. The catalyst is then removed by filtration over celite and the solvent removed from the resulting filtrate to afford a crude oil which is purified by flash chromatography on silica gel (5% MeOH/CH2Cl2). The desired product 7 is obtained as a white foam (9.71 g, 93% yield): 1H NMR δ (CDCl3) 7.02-7.20 (m, 4H), 6.71 (br s, 1H), 6.37 (br d, J=8.8 Hz, 1H), 4.16-5.13 (br m, 4H), 3.10-3.71 (br m, 3H), 2.64-2.84 (br m, 7H), 1.58-2.11 (br m, 7H), 1.46 (s, 9H), 1.30 (d, J=7.1 Hz, 2H), 0.86-1.02 (br m, 3H), 0.75 (d, J=6.7 Hz, 2H), 0.53 (br d, J=6.7 Hz, 2H); LCMS (APCl+) 544.9 (MH+), 444.6 (MH+-BOC), 260.2 (MH+-dipeptide, 100%); HPLC (C8 column) 95.2%.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.CC1(C)C(C)(C)OB([C:46]2[CH:51]=[CH:50][C:49]([NH:52][C:53]([CH:55]3[CH2:57][CH2:56]3)=[O:54])=[CH:48][CH:47]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH:55]1([C:53]([NH:52][C:49]2[CH:50]=[CH:51][C:46]([C:2]3[N:3]=[C:4]4[C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=5[NH:8][C:7]5[N:15]=[CH:16][CH:17]=[CH:18][C:6]=5[N:5]4[C:19]=3[C:20]3[CH:25]=[CH:24][C:23]([C:26]4([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:36])[CH3:34])[CH2:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)=[CH:47][CH:48]=2)=[O:54])[CH2:56][CH2:57]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Br)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reactant: CC1(C)OB(c2ccc(NC(=O)C3CC3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(NC(=O)C5CC5)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 160 °C
Yield: 94.3 %

Procedure:
A mixture of tert-butyl {1-[4-(2-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (50.0 mg, 0.0895 mmol), N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarboxamide (38.6 mg, 0.134 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (6.34 mg, 0.00895 mmol) and 2 M Na2CO3 (0.0895 mL, 0.179 mmol) in DMF (1.00 mL) was heated at 160° C. under microwave irradiation for 1 hour. After cooling to room temperature, the mixture was diluted with water and extracted with CHCl3 (×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by PTLC (CHCl3/MeOH=9:1) to afford desired product (53.9 mg, 94.3%) as pale yellow solid. 1HNMR (CDCl3) 500 MHz δ: 8.15 (dd, J=7.7, 1.4 Hz, 1H), 8.02-7.97 (m, 1H), 7.70 (br s, 1H), 7.55-7.48 (m, 2H), 7.45-7.38 (m, 2H), 7.36-7.31 (m, 2H), 7.30-7.25 (m, 1H), 7.16-7.10 (m, 3H), 6.95 (d, J=8.0 Hz, 1H), 6.83-6.74 (m, 1H), 6.58 (dd, J=7.7, 4.9 Hz, 1H), 6.55-6.49 (m, 1H), 5.26 (br s, 1H), 2.59-2.24 (m, 4H), 2.19-2.06 (m, 1H), 1.95-1.79 (m, 1H), 1.57-1.19 (m, 10H), 1.09-1.02 (m, 2H), 0.84-0.75 (m, 2H).
Reaction SMILES: C[O:2][P:3]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[O:4][CH3:5].[C:12]([C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[CH2:19]Cl)([CH3:15])([CH3:14])[CH3:13]>C1(C)C=CC=CC=1>[CH3:5][O:4][P:3]([CH2:19][C:18]1[CH:17]=[C:16]([C:12]([CH3:13])([CH3:15])[CH3:14])[C:23]([OH:24])=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:21]=1)([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:2]
Reactant: CC(C)(C)c1cc(CCl)cc(C(C)(C)C)c1O
Reactant: COP(OC)C1CCCCC1
Solvent: Cc1ccccc1
Product: COP(=O)(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C1CCCCC1
Yield: 51.2 %

Procedure:
A mixture of 10.47 grams (59 mmol) of dimethylcyclohexylphosphonite with 15.14 grams (59 mmol) of 3,5-di-tert-butyl-4-hydroxybenzyl chloride (CAS REG # 955-01-1) in 45 mL of toluene is refluxed for 2 hours and is cooled. The resultant precipitated crystals are collected by filtration, washed with toluene, then hexane and are dried under vacuum to obtain 11.5 grams (51% yield) of (3,5-di-tert-butyl-4-hydroxy-benzyl)-cyclohexyl-phosphinic acid methyl ester as a white solid mp 149-150° C.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].Cl.[O:12]([NH2:14])[CH3:13]>>[CH3:13][O:12][N:14]=[CH:7][C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CON
Agent: Cl
Product: CON=Cc1ccc(C#N)cc1
Yield: 96 %

Procedure:
Reaction of 4-cyanobenzaldehyde with methoxylamine hydrochloride as described in the preparation of Compound 44-A gave the title oxime ether as a white solid (96% yield), (Gordon, M. S. et al., J. Org. Chem., 49, 1984, 97–100). 1HNMR indicated a 95:5 mixture of E- to Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 4.02 (3H, s, OCH3), 7.07 (4H, m, aromatics), 8.06 (1H, s, CH).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].O.[NH2:10][NH2:11]>CCO>[CH:7]1[CH:8]=[C:3](/[C:1](/[NH2:2])=[N:10]\[NH2:11])[N:4]=[CH:5][CH:6]=1
Reactant: NN
Reactant: N#Cc1ccccn1
Solvent: O
Solvent: CCO
Product: N/N=C(/N)c1ccccn1
Temperature: 0 °C
Reaction time: 18 h
Yield: 137.5 %

Procedure:
2-Cyano pyridine (500 mg, 1.923 mmol) and Hydrazine hydrate (252 mg, 1.923 mmol) were mixed together in EtOH (3 ml). The clear solution was left at 15° C. (in refrigerator) for 18 h (Monitored by TLC). Ethanol was concentrated under reduced pressure and then the reaction mixture was diluted with diethyl ether (50 ml) and water. The diethyl ether layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to 1/5th Volume. The ethereal solution was cooled to 0° C. and the obtained solid precipitate was collected over the filtration and dried under vacuum, which gave the 2-pyridine Amidrazone (360 mg).