Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][C:11]([OH:15])([C:13]#[CH:14])[CH3:12]>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.[Cu]I>[CH3:10][C:11]([OH:15])([CH3:12])[C:13]#[C:14][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)O
Reactant: O=Cc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CC(C)(O)C#Cc1ccc(C=O)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
4-Bromobenzaldehyde (3.0 g, 16 mmol), Pd(PPh3)2Cl2 (110 mg, 0.170 mmol) and CuI (16 mg, 0.07 mmol) were placed in a Schlenk flask. The flask was then evacuated and purged with argon (3 times) on the Schlenk line. Then freshly distilled and degassed TEA (32 mL) was added, and after purging with argon, 2-methyl-3-butyn-2-ol (1.90 mL, 19.4 mmol) was added. The reaction mixture was stirred for 2 h at 40° C. (The progress of the reaction was monitored by GC-MS). The reaction mixture was evaporated to dryness and then chromatographed (silica, CH2Cl2). Bulb-to-bulb distillation (93-95° C., 0.001 mm Hg) gave a pale yellowish oil (2.90 g, 95%). 1H NMR (CDCl3) δ 1.61 (s, 6H), 2.23 (brs, 1H), 7.52 (AB/2, J=8.1 Hz, 2H), 7.79 (AB/2, J=8.1 Hz, 2H), 9.02 (s, 1H); 13C NMR δ 31.9, 66.1, 81.9, 98.8, 129.8, 130.1, 132.7, 135.9, 192.3; IR (film) v (cm−1) 790.4, 830.1, 906.3, 963.4, 1014.3, 1046.1, 1165.9, 1207.0, 1273.4, 1303.0, 1373.0, 1457.6, 1563.8, 1603.6, 1700.0, 2228.1, 2735.0, 2837.8, 2934.1, 2982.2, 3413.3; MS (EI+) m/z 188 (M+, 35%), 173 (100%), 159 (10%); EI-MS obsd 188.0835, calcd exact mass 188.0837 (C12H12O2).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13](#[N:17])[CH:14]([CH3:16])[CH3:15].[Br:18][C:19]1[CH:32]=[CH:31][C:22]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])=[CH:21][C:20]=1[CH2:33]Br.[Cl-].[NH4+]>C1COCC1.CCCCCC>[Br:18][C:19]1[CH:32]=[CH:31][C:22]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])=[CH:21][C:20]=1[CH2:33][C:14]([CH3:16])([CH3:15])[C:13]#[N:17]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)c(CBr)c1
Reactant: CC(C)C#N
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C#N)Cc1cc(O[Si](C)(C)C(C)(C)C)ccc1Br
Reaction time: 0.17 h

Procedure:
Under a nitrogen atmosphere, to a solution of diisopropylamine (0.70 mL) in THF (15 mL) was added a 1.6 M solution of n-butyllithium in hexane (3.0 mL) at 0° C., and the mixture was stirred for 10 min. Isobutyronitrile (0.47 mL) was added at −78° C., and the mixture was stirred for 30 min. A solution of (4-bromo-3-(bromomethyl)phenoxy) (tert-butyl)dimethylsilane (1.00 g) in THF (5.0 mL) was added, and the mixture was stirred at −78° C. for 2 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (905 mg) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26])[CH2:6][O:7][C:8]1[C:13]([CH2:14]O)=[CH:12][CH:11]=[CH:10][N:9]=1.[CH2:33]([N:35](CC)CC)C.CS(Cl)(=O)=O.[C-]#N.[Na+]>O.CS(C)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[O:24][C:25]=1[CH3:26])[CH2:6][O:7][C:8]1[C:13]([CH2:14][C:33]#[N:35])=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: COc1cc(COc2ncccc2CO)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(COc2ncccc2CC#N)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a mixture of [2-[-3-methoxy-4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]methanol (540 mg), triethylamine (0.350 mL) and ethyl acetate (50 mL) was dropwise added methanesulfonyl chloride (0.145 mL) under ice-cooling and the mixture was stirred at room temperature for 0.5 hr. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give an oil. To a mixture of this oil and dimethyl sulfoxide (10 mL) was added a solution of sodium cyanide (160 mg) in water (1 mL) at room temperature and the mixture was stirred at room temperature for 2 hrs. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained crystals were recrystallized from ethyl acetate-hexane to give crystals (438 mg, 79%) of 2-[2-[3-methoxy-4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetonitrile. melting point: 108-109° C.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[CH3:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[CH3:29])[NH2:25]>ClCCl.N1C=CC=CC=1>[CH3:21][C:22]1[CH:23]=[C:24]([NH:25][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:25][C:24]2[CH:26]=[CH:27][C:28]([CH3:29])=[C:22]([CH3:21])[CH:23]=2)=[O:13])[CH:26]=[CH:27][C:28]=1[CH3:29]
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: Cc1ccc(N)cc1C
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccccc2SSc2ccccc2C(=O)Nc2ccc(C)c(C)c2)cc1C
Yield: 16.8 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (1.12 g, 3.26 mmol) in 25 mL of dichloromethane and 3,4-dimethylaniline (0.79 g, 6.52 mmol) in 8 mL of pyridine. The crude product was triturated with ethyl ether and filtered to yield 0.28 g of the title compound, mp 224°-227° C.
Reaction SMILES: [CH3:1][N:2]([CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)C(=O)C(F)(F)F.[OH-].[Na+].[ClH:18].C(O)C>CO.O>[ClH:18].[ClH:18].[CH3:1][NH:2][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: CN(Cc1cccnc1)C(=O)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Solvent: O
Product: CNCc1cccnc1
Yield: 95 %

Procedure:
3.71 g of N-methyl-N-(3-pyridylmethyl)trifluoroacetic acid amide was dissolved in a mixture of 20 ml methanol and 20 ml water, and then stirred with 1.36 g of sodium hydroxide at room temperature for 6 hours. The reaction mixture was made acidic (pH 2) with concentrated hydrochloric acid on ice, and the resulting acidic solution was concentrated under reduced pressure to give a residue. After addition of ethanol, the residue was filtered to remove the precipitated inorganic salts. The filtrate was concentrated under reduced pressure, dried and then recrystallized from methanol/ethanol to give 3-(methylaminomethyl)pyridine dihydrochloride (3.16 g, 95%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([N:21]=[C:32]=[O:34])=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(N)cc2)COC1(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(N=C=O)cc2)COC1(C)C
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 253.7 %

Procedure:
To a stirred suspension of (S)-4-[2-(4-amino-phenyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (600 mg, example 14 (b)) in dichloromethane (10 ml) were added sequentially triethylamine (0.52 ml) and triphosgene (206 mg) and the mixture was heated at 50° C. for 18 h. The mixture was then concentrated in vacuo and to the residue was added diethyl ether. After stirring for 10 min at room temperature the resulting crystals were removed by filtration. The filtrate was concentrated in vacuo to give (S)-4-[2-(4-isocyanato-phenyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (610 mg, 94%) as a yellow oil which was used immediately in the next step without further purification.
Reaction SMILES: [CH:1](=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([NH2:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17].O>C1(C)C=CC=CC=1>[C:4]1([CH:3]=[CH:2][CH:1]=[N:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][N:18]=[CH:1][CH:2]=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=CC=Cc1ccccc1
Reactant: NCCCCCCN
Solvent: Cc1ccccc1
Solvent: O
Product: C(=Cc1ccccc1)C=NCCCCCCN=CC=Cc1ccccc1
Yield: 97 %

Procedure:
Cinnamaldehyde (198.2 g, 1.5 mole) is carefully added to a solution of 1,6-hexanediamine (87.2 g, 0.75 mole) in toluene (400 ml). Slight exotherm to 60° C. is observed. The resulting solution is heated at reflux until water (27 ml, 1.5 mole) is evolved. Evaporation of the solution gives 250.7 g of a brown viscous oil. 1H NMR: δ 1.0-2.85 (broad bands 8H); δ 3.6 (triplet 4 H); δ 6.82-8.22 (broad multiplete 16 H). Elemental analysis: Theory for C24H28N2 : C,83.72; H,8.14; N,8.14%. Found: C,83.61; H,8.35; N,8.05%.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([Cl:16])=[CH:13][CH:14]=2)[NH:9][C:8](=[O:17])[C:7]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([OH:3])=O.Cl.[CH3:25][O:26][NH2:27].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>O1CCCC1.O.C(N(CC)CC)C>[Cl:16][C:12]1[CH:11]=[C:10]2[C:15]([C:6]([O:5][CH2:4][C:1]([NH:27][O:26][CH3:25])=[O:3])=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8](=[O:17])[NH:9]2)=[CH:14][CH:13]=1
Reactant: O=C(O)COc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12
Reactant: CON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CONC(=O)COc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 6 %

Procedure:
To a solution of 4-carboxymethoxy-7-chloro-3-phenyl-2(1H)-quinolone (Example 15, 1.83 g) in tetrahydrofuran (150 ml) under nitrogen at room temperature, was added triethylamine (3.65 ml), O-methyl hydroxylamine hydrochloride (0.96 g), 1-hydroxybenzotriazole (1.15 g) and 1-(3 dimethylaminopropyl)-3-ethyl carbodiimide (1.73 g). The reaction mixture was stirred at room temperature for 16 h, then poured into water (150 ml) and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with water (1×100 ml), 1N citric acid (1×100 ml), brine (1×100 ml) and a saturated sodium hydrogen carbonate solution (1×50 ml), dried (MgSO4), filtered and the solvent was removed in vacuo to leave a solid residue. Recrystallisation from ethyl acetate gave the title compound (0.12 g). Mp 205°-207° C. m/z (CI+), 359, (m+1). 1H NMR (360 MHz, DMSO-d6) δ 3.32 (3H, s, NHOCH3), 3.93 (2H, s, OCH2CONHOCH3), 7.23 (1H, dd, J=8.63 Hz, J=1.83 Hz, 6-H), 7.36-7.45 (6H, m, Ph+8-H), 8.00 (1H, d, J=8.63 Hz, 5-H), 11.26 (1H, bs, OCH2CONHOCH3), 11.94 (1H, bs, NH). Found: C, 60.57; H, 4.26; N, 7.82; C18H15N2O4Cl requires C, 60.26; H, 4.21; N, 7.81%.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][C:14]=2[CH2:32][CH3:33])[N:3]=1.[C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:42][C:43]([O:45][CH3:46])=[O:44])#[CH:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[CH2:32]([C:14]1[CH:15]=[C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[CH:17]=[CH:18][C:13]=1[NH:12][C:4]1[N:3]=[C:2]([C:35]#[C:34][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[CH2:42][C:43]([O:45][CH3:46])=[O:44])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=1)[CH3:33]
Reactant: CCc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Reactant: C#Cc1ccccc1CC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(C#Cc2ccccc2CC(=O)OC)n1
Temperature: 120 °C
Yield: 85.5 %

Procedure:
A mixture of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-ethylphenyl)piperidine-1-carboxylate (I41) (283 mg, 0.584 mmol), methyl 2-(2-ethynylphenyl)acetate (I4) (122 mg, 0.700 mmol), copper(I) iodide (17 mg, 15 mol %), triphenylphosphine (23 mg, 15 mol %), bis(triphenylphosphine)palladium(II) chloride (41 mg, 10 mol %), triethylamine (0.33 mL, 2.3 mmol) and DMF (3 mL) was degassed with a nitrogen then heated under microwave irradiation (120° C./15 min). The cooled mixture was poured into water (30 mL) and extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed with brine (2×50 mL), dried over sodium sulfate and evaporated. Chromatography (12 g silica cartridge, 0-80% ethyl acetate/petroleum benzine 40-60° C.) gave the title compound (I42) (311 mg, 86% yield) as a brown oil; 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 7.73-7.65 (m, 2H), 7.46-7.28 (m), 7.15-7.08 (m), 4.25 (s, 2H), 3.95 (s, J=9.6 Hz, 2H), 3.70 (s, 3H), 2.80 (t, J=12.1 Hz, 2H), 2.70-2.59 (m, 3H), 1.84 (d, J=12.9 Hz, 2H), 1.65 (td, J=12.8, 4.1 Hz, 2H), 1.49 (s, 9H), 1.25 (t, J=7.6 Hz, 3H). LCMS: rt 7.01 min; m/z 623.1 [M+H]+, 567.1 [M-tBu+2H]+, 523.1 [M-Boc+2H]+; m/z 621.2 [M−H]−.
Reaction SMILES: CS[C:3]1[NH:12][C:11](=[O:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.[N:14]1([C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(O)CC(C)C.C(#N)C>[N:22]1([C:20]([N:14]2[CH2:15][CH2:16][N:17]([C:3]3[NH:12][C:11](=[O:13])[C:10]4[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=4[N:4]=3)[CH2:18][CH2:19]2)=[O:21])[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1
Reactant: CSc1nc2c(c(=O)[nH]1)CCCC2
Reactant: O=C(N1CCNCC1)N1CCOCC1
Solvent: CC#N
Solvent: CC(C)CCO
Product: O=C(N1CCOCC1)N1CCN(c2nc3c(c(=O)[nH]2)CCCC3)CC1

Procedure:
2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51 mmol) and piperazinocarboxylic acid morpholide (152.3 mg; 0.76 mmol) are reacted in isoamyl alcohol (1.5 ml) in accordance with the procedure for Example 1 (reaction time 8 h) and worked up. The crystals obtained are dissolved in acetonitrile and water and freeze-dried; yield: 38 mg (21%), crystals;
Reaction SMILES: [H][H].[CH2:3]([OH:11])[CH2:4][C:5]#[C:6][CH2:7][CH2:8][CH2:9][CH3:10].N1C=CC=CC=1>CCCCCC.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[CH2:3]([OH:11])[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: [H][H]
Reactant: CCCCC#CCCO
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CCCC/C=C\CCO

Procedure:
Hydrogen gas was blown into a solution prepared by dissolving 126 g of 3-octyn-1-ol in 100 ml of n-hexane with admixture of 10 g of a Lindlar catalyst and 10 g of pyridine and the introduction of hydrogen was continued for about 4 hours when absorption of hydrogen had ceased. Removal of solid matter from the reaction mixture by filtration and stripping of n-hexane gave cis-3-octen-1-ol, which was dissolved in a mixture of 250 g of methylene chloride and 111 g of triethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=O)[NH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:10]3[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:6]=2[CH:27]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:29].P(Cl)(Cl)(Cl)=O.C1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:7]1[C:6]2[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:11]2[C:12]([Cl:29])=[N:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:10]2[CH2:9][N:8]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COC(=O)c1[nH]c(=O)n2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1nc(Cl)n2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A stirred mixture of 10 g (0.025 mole) of 8-chloro-6-(2-chlorophenyl)-1,2-dihydro-1-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid, methyl ester, 1 g (0.005 mole) of phosphorus pentachloride and 250 ml of phosphorus oxychloride was refluxed under a drying tube for 44 hrs. Benzene (250 ml) was added and the dark solution was evaporated in vacuo at 50°-60°. Another 250 ml of benzene was added and the solution was again evaporated to dryness at reduced pressure. The residue was dissolved in 250 ml of methylene chloride and cooled in an ice bath. Ammonia was bubbled into the cold solution for 5 min to give a tan solid. Stirring at room temperature was continued for 15 min. The mixture was filtered and evaporated at reduced pressure to give a brown gum which solidified when triturated with 75 ml of boiling ether. This solid was dissolved in about 50 ml of methylene chloride and filtered over neutral alumina. Eluted first with methylene chloride and then with 30% ethyl acetate in methylene chloride. Evaporation of the ethyl acetate methylene chloride fractions gave a tan solid which was recrystallized from ethyl acetate to give off-white prisms with mp 200°-202°. Uv λ sh 213 mμ (ε=44,600) infl 240 (27,500) infl 260 (20,000) infl 300 (1850) ir (CHCl3) 1717 cm-1 (COOCH3).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:31][CH2:32][CH3:33])[N:10]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]([O:23]C(OC(C)(C)C)=O)[C:16](=O)[O:17]C(C)(C)C)[C:6]=2[C:5]([CH3:34])=[C:4]([CH3:35])[N:3]=1.Cl.O1CCOC[CH2:38]1.C(N(CC)CC)C.C(OC(=O)C)(=O)C>ClCCl>[NH2:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:31][CH2:32][CH3:33])[N:10]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]([OH:23])[C:16](=[O:17])[CH3:38])[C:6]=2[C:5]([CH3:34])=[C:4]([CH3:35])[N:3]=1
Reactant: CCCc1nc2c(N)nc(C)c(C)c2n1CCCCN(OC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: C1COCCO1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1nc2c(N)nc(C)c(C)c2n1CCCCN(O)C(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The preparation of tert-butyl 4-(4-amino-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl[(tert-butoxycarbonyl)oxy]carbamate is described in Parts A-F of Example 14. A solution of 4M hydrochloric acid in dioxane (1.8 mL, 7.2 mmol, 20 eq) is added to a solution of tert-butyl 4-(4-amino-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl[(tert-butoxycarbonyl)oxy]carbamate (175 mg, 0.36 mmol, 1.0 eq) in dichloromethane (4 mL) and stirred at ambient temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the resulting crude material was dissolved in 1-methyl-2-pyrrolidinone (NMP) (4 mL) and cooled to −8° C. Triethylamine (0.500 mL, 10 eq) and acetic anhydride (0.034 mL, 0.36 mmol) were sequentially added dropwise to the reaction mixture and stirred for 1 hour. The crude reaction mixture was concentrated reduced pressure at 70° C. The residue was partitioned between saturated aqueous sodium carbonate and chloroform and the phases were separated. The aqueous phase was back-extracted with chloroform and the combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford crude material. The material was purified by column chromatography on a BIOTAGE HORIZON High-Performance Flash Chromatography instrument (silica gel, eluting with 10-50% CMA in chloroform) and trituration with chloroform/ethyl acetate. The resulting material was filtered and washed with ethyl acetate and dried under high vacuum to afford 0.025 g of N-[4-(4-amino-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]-N-hydroxyacetamide as a white powder, mp 164.0-166.0° C. MS (APCI) m/z 334 (M)+; Anal. Calcd for C17H27N5O2.0.05CHCl3 C, 60.34; H, 8.03; N, 20.64. Found: C, 60.05; H, 7.97; N, 20.43.
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[Cs+].[Cs+].Br[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]=[C:19]([C:21]3[C:25]([CH2:26][CH2:27][CH3:28])=[C:24]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:23][N:22]=3)[O:18][N:17]=2)=[CH:12][CH:11]=1.[I-].[Na+].[CH3:37][N:38]1[C:42](=O)[CH2:41][CH2:40][CH2:39]1>>[C:29]1([C:24]2[O:23][N:22]=[C:21]([C:19]3[O:18][N:17]=[C:16]([C:13]4[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][N:38]5[CH2:37][CH2:42][CH2:41][C@H:40]([C:1]([OH:2])=[O:4])[CH2:39]5)=[CH:11][CH:12]=4)[N:20]=3)[C:25]=2[CH2:26][CH2:27][CH3:28])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C([O-])[O-]
Reactant: CN1CCCC1=O
Reactant: CCCc1c(-c2nc(-c3ccc(CCBr)cc3)no2)noc1-c1ccccc1
Agent: [Cs+]
Agent: [I-]
Agent: [Na+]
Product: CCCc1c(-c2nc(-c3ccc(CCN4CCC[C@H](C(=O)O)C4)cc3)no2)noc1-c1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a mixture of (S)-piperidine-3-carboxylic acid, HCl (29.5 mg, 0.178 mmol) in NMP (2 mL) was added cesium carbonate (97 mg, 0.297 mmol). The reaction mixture was stirred for 30 minutes. Next, 3-(4-(2-bromoethyl)phenyl)-5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazole (26 mg, 0.059 mmol) and sodium iodide (2 mg, 0.013 mmol) were added. The reaction mixture was heated at 80° C. overnight. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30 mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 20 mL/min. The resulting material was 4mg of (S)-1-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenethyl)piperidine-3-carboxylic acid as a TFA salt. MS (m+1)=487. HPLC Peak RT=3.67 minutes (Analytical Method A). 1H NMR (400 MHz, MeOH-d3) δ ppm 8.03 (2H, m), 7.71 (2H, dd, J=7.91, 1.54 Hz), 7.46-7.56 (3H, m), 7.39 (2H, m, J=8.57 Hz), 4.26-4.49 (2H, m), 3.27 (1H, dd, J=12.96, 3.95 Hz), 3.05-3.15 (3H, m), 2.86-3.04 (5H, m), 2.65-2.81 (1H, m), 1.89-2.03 (1H, m), 1.57-1.77 (5H, m), 0.95 (3H, t, J=7.36 Hz).
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[CH2:9]1.[CH:16](O)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[C:17]1([CH:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:15][CH2:14][CH:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: OCC1CCCNC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(C(OCC2CCCNC2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.6 %

Procedure:
Trifluoroacetic acid (20 ml) was added cautiously to a vigorously stirred solution of piperidine-3-methanol (5.75 g, 50 mmol) in dichloromethane (20 ml) and the mixture treated with benzhydrol (9.2 g, 50 mmol) portionwise over 5 minutes, stirred at room temperature for 2 hours and evaporated. The residue was dissolved in dioxane (50 ml) and the solution treated with 4M aqueous sodium hydroxide solution (100 ml), stirred at room temperature for 2 hours, diluted with ether and water and the layers separated. The organic layer was washed with water and extracted into 2M hydrochloric acid. The acidic extract was washed with ether, basified with solid sodium carbonate, extracted into ether, washed with water, dried over magnesium sulphate and evaporated to give the title compound (4.31 g) as a pale yellow oil which was characterised by its 1H-NMR spectrum.