Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([OH:14])=[O:13].C(Cl)(=O)C(Cl)=O.[CH3:21][C:22]([CH3:25])([O-])[CH3:23].[K+]>ClCCl.CN(C)C=O.O1CCCC1>[C:22]([O:13][C:12]([C:7]1[C:8]2[C:3](=[C:2]([Br:1])[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][CH:6]=1)=[O:14])([CH3:25])([CH3:23])[CH3:21]
Reactant: CC(C)(C)[O-]
Reactant: O=C(O)c1cccc2c(Br)cccc12
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cccc2c(Br)cccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 90.8 %

Procedure:
To a suspension of 5-bromo-1-naphtoic acid (Example 9.1) (10.8 g) in dichloromethane (93 ml) containing 3 drops of dimethylformamide was added oxalyl chloride (4 ml) and the reaction mixture stirred at ambient temperature for 6 hours. The solution was concentrated to afford a white solid which was re-dissolved in tetrahydrofuran. The solution was cooled to 2° C. and a solution of potassium tert-butoxide (7.2 g) in tetrahydrofuran (148 ml) was added dropwise and the reaction mixture stirred at ambient temperature for 3 hours. The solution was poured onto ice and extracted with ethyl acetate. The combined organic extracts were washed with water, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate) to give 5-bromo-1-naphtoic acid tert-butyl ester (12 g). 1H-NMR (CDCl3, 400 MHz): 8.82 (d, 1H), 8.46 (d, 1H), 8.11 (d, 1H), 7.72 (d, 1H), 7.60 (m, 1H), 7.40 (m, 1H), 1.70 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.[CH:15]([Si:18]([C:25]#[CH:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16].ClCCl>C(N(CC)CC)C.[Cu](I)I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:14][C:5]1[CH:4]=[CH:3][C:2]([C:26]#[C:25][Si:18]([CH:15]([CH3:17])[CH3:16])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])=[CH:7][C:6]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: C#C[Si](C(C)C)(C(C)C)C(C)C
Reactant: Fc1ccc(Br)cc1N1CCOCC1
Agent: I[Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[Si](C#Cc1ccc(F)c(N2CCOCC2)c1)(C(C)C)C(C)C
Yield: 99.6 %

Procedure:
To a CEM snap top microwave vial (10 ml) equipped with a magnetic stir bar (3×10 mm) was added 4-(5-bromo-2-fluorophenyl)morpholine (390 mg, 1.50 mmol) in triethylamine (1.5 mL). Copper iodide (12 mg, 0.060 mmol), Tetrakis(triphenylphosphine) palladium (35 mg, 0.030 mmol) and triisopropylsilyl-acetylene (0.390 mg, 2.14 mmol) were added at room temperature. The reaction was capped and irradiated in a CEM Explorer microwave at 80° C. for 30 minutes then forced air-cooled. The crude material was loaded onto silica gel and chased with dichloromethane. Purification by chromatography (hexanes) afforded 540 mg of an oil (quant); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06-1.10 (m, 21H) 3.00 (t, J=4.6 Hz, 4H) 3.71 (t, J=4.6 Hz, 4H) 7.01 (dd, J=8.5, 2.0 Hz, 1H) 7.08 (ddd, J=4.9, 2.9, 2.6 Hz, 1H) 7.11-7.18 (m, 1H); MS (ES) m/z 362.2 [M+H]+
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.[C:12]1(=[O:28])[N:16]([CH2:17][CH2:18][CH2:19][C:20](=[S:22])[NH2:21])[C:15](=[O:23])[C:14]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:13]12>>[C:15]1(=[O:23])[N:16]([CH2:17][CH2:18][CH2:19][C:20]2[S:22][C:2]3[CH2:10][C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[C:3]=3[N:21]=2)[C:12](=[O:28])[C:13]2=[CH:27][CH:26]=[CH:25][CH:24]=[C:14]12
Reactant: O=C1c2ccccc2CC1Br
Reactant: NC(=S)CCCN1C(=O)c2ccccc2C1=O
Product: O=C1c2ccccc2C(=O)N1CCCc1nc2c(s1)Cc1ccccc1-2

Procedure:
2-Bromo-1-indanone, 4-phthalimidobutanethioamide
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH2:9])=[O:8])[N:6]=1.[C:10]([C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[N:19]([C:25]1[CH:35]=[CH:34][CH:33]=[C:32](B3OC(C)(C)C(C)(C)O3)[C:26]=1[CH2:27][O:28]C(=O)C)[N:18]=[CH:17]2)([CH3:13])([CH3:12])[CH3:11]>>[C:10]([C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[N:19]([C:25]1[C:26]([CH2:27][OH:28])=[C:32]([C:2]3[S:3][CH:4]=[C:5]([C:7]([NH2:9])=[O:8])[N:6]=3)[CH:33]=[CH:34][CH:35]=1)[N:18]=[CH:17]2)([CH3:13])([CH3:11])[CH3:12]
Reactant: NC(=O)c1csc(Br)n1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)ccc2c1=O
Product: CC(C)(C)c1ccc2c(=O)n(-c3cccc(-c4nc(C(N)=O)cs4)c3CO)ncc2c1
Yield: 25 %

Procedure:
This compound was prepared with the same method as described in Example 1 by using 2-bromothiazole-4-carboxylic acid amide (intermediate-2) and acetic acid 2-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl ester (intermediate 4). The desired compound was prepared in two steps (25% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.56 (s, 1H), 8.41 (s, 1H), 8.24 (d, J=8.4 Hz, 1H), 8.05-8.00 (m, 2H), 7.82 (dd, J=1.8, 7.2 Hz, 1H), 7.61-7.58 (m, 2H), 4.54-4.45 (m, 2H), 1.41 (s, 9H). LC-MS calcd for C23H22N4O3S (m/e) 434.14, obsd 435 [M+1]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH2:18][C:19](=[O:35])[NH:20][C:21]4[CH:27]=[C:26]([C:28]5[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=5)[CH:25]=[CH:24][C:22]=4[N:23]=3)[CH:12]=2)[S:9][CH:10]=1)=[O:5])C.[OH-].[K+]>CO.CS(C)=O>[F:34][C:31]1[CH:32]=[CH:33][C:28]([C:26]2[CH:25]=[CH:24][C:22]3[N:23]=[C:17]([C:13]4[CH:12]=[C:11]([C:8]5[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=5)[CH:16]=[CH:15][CH:14]=4)[CH2:18][C:19](=[O:35])[NH:20][C:21]=3[CH:27]=2)=[CH:29][CH:30]=1
Reactant: CCOC(=O)c1csc(-c2cccc(C3=Nc4ccc(-c5ccc(F)cc5)cc4NC(=O)C3)c2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CO
Product: O=C1CC(c2cccc(-c3nc(C(=O)O)cs3)c2)=Nc2ccc(-c3ccc(F)cc3)cc2N1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
To a solution of 2-{3-[7-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-phenyl}-thiazole-4-carboxylic acid ethyl ester (Example 153) (49 mg, 0.1 mmol) in a mixture of MeOH (1 mL) and DMSO (1.5 mL) was added 2N KOH (1 mL, 2 mmol). The mixture was stirred at 23° C. for 0.5 h and then partitioned between ethyl acetate and H2O. The pH of the aqueous phase was set to 3 by the addition of 3N HCl and then stirred in the ice-bath for 0.5 h. The precipitate was collected by filtration, triturated with EtOH/Et2O (1/1) and dried, to give the title compound as light yellow solid (25 mg).
Reaction SMILES: ClC(OCC(C)C)=O.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11](/[CH:15]=[CH:16]/[C:17](O)=[O:18])[CH:10]=1.CN1CCOCC1.[BH4-].[Na+]>COCCOC.O>[N:9]1[CH:14]=[CH:13][CH:12]=[C:11](/[CH:15]=[CH:16]/[CH2:17][OH:18])[CH:10]=1
Reactant: O=C(O)/C=C/c1cccnc1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: COCCOC
Solvent: O
Product: OC/C=C/c1cccnc1
Reaction time: 0.5 h
Yield: 22.1 %

Procedure:
Isobutyl chloroformate (4.4 ml) was added dropwise to a suspension of (E)-3-(3-pyridyl)acrylic acid (5.0 g) and N-methylmorpholine (4.05 ml) in 1,2-dimethoxyethane (50 ml) under −18° C. After being stirred at the same temperature for 0.5 hour, a solution of sodium borohydride (1.86 g) in water (10 ml) was added to the mixture all at once. The resulting mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate as eluent. The fractions containing the objective compound were collected and evaporated under reduced pressure to give (E)-3-(3-pyridyl)-2-propen-1-ol (1.0 g) as an oil.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].P(=O)([O-])[O-].C([Li])CCC.[CH:17]1([C:27](OC)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>O1CCCC1.CCCCCC.C(O)(=O)C>[O:28]=[C:27]([CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COC(=O)C1CCCCCCCCC1
Reactant: COP(C)(=O)OC
Agent: O=[PH]([O-])[O-]
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COP(=O)(CC(=O)C1CCCCCCCCC1)OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 49.6 g (0.40 mole) dimethyl methylphosphonate (Aldrich) in 500 ml dry tetrahydrofuran is cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution is added 188 ml of 2.34 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 18 minutes at such a rate that the reaction temperature never rises above -65°. After an additional 5 minutes stirring at -78°, 25.6 g (0.20 mole) methyl cyclodecanecarboxylate is added dropwise at a rate that keeps the reaction temperature less than -70° (20 minutes). After 1.0 hour at -78° the reaction mixture is allowed to warm to ambient temperature, neutralized with 25 ml acetic acid and rotary evaporated to a white gel. The gelatinous material is taken up in 75 ml water, the aqueous phase extracted with 100 ml portions of chloroform (3x), the combined organic extracts are backwashed (50 cc H2O), dried (MgSO4), and concentrated (water aspirator) to a crude residue and distilled to give dimethyl 2-oxo-2-cyclodecylethylphosphonate.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]=[CH:28][CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].Cl>C1COCC1.CCO>[CH3:26][C:23]1[C:22]([CH:27]=[CH:28][CH2:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3[CH:13]=[CH:14][C:9]([C:6]4([C:4]([OH:5])=[O:3])[CH2:8][CH2:7]4)=[CH:10][CH:11]=3)=[CH:16][CH:17]=2)[O:25][N:24]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C=CCCc4ccccc4)cc3)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1C=CCCc1ccccc1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
1-{4′-[3-Methyl-4-(4-phenyl-but-1-enyl)-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester (0.072 g, 0.15 mmol) in THF (2 mL) and EtOH (1 mL) was treated with 3 N aqueous NaOH (0.75 mL, 2.25 mmol) and the reaction was stirred at 75° C. overnight. The mixture was acidified with 1 N aqueous HCl (2.25 mL) and extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by preparative HPLC to give the title compound.
Reaction SMILES: O=[C:2]1[CH2:8][C@H:7]2[N:4]([C:5](=[O:26])[C@@H:6]2[C:9]([CH3:25])([O:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[O:13])[CH3:10])[C@H:3]1[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)=[O:28].C(N(C(C)C)CC)(C)C.P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[SH:66][CH2:67][CH2:68][NH:69][C:70](=[O:72])[CH3:71]>CN(C1C=CN=CC=1)C.C(#N)C.C(OCC)(=O)C>[C:70]([NH:69][CH2:68][CH2:67][S:66][C:2]1[CH2:8][C@H:7]2[N:4]([C:5](=[O:26])[C@@H:6]2[C:9]([CH3:10])([O:11][C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[O:13])[CH3:25])[C:3]=1[C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=1)=[O:28])(=[O:72])[CH3:71]
Reactant: CC(=O)NCCS
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Agent: CN(C)c1ccncc1
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)NCCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H](C(C)(C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)[C@H]2C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To a solution of 4-nitrobenzyl(2R,5R,6S)-3,7-dioxo-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)-ethyl]-1-azabicyclo[3.2.0]heptane-2-carboxylate (47.8 mg) and 4-(N,N-dimethylamino)pyridine (1.08 mg) in acetonitrile (2.39 ml) was added dropwise a solution of di-isopropylethylamine (18.5 μl) in acetonitrile (166.5 μl) followed by addition of a solution of diphenyl chlorophosphate (19.2 μl) in acetonitrile (172.8 μl) at 0° C. After stirring for an hour at 0° C., a solution of di-isopropylethylamine (61.5 μl) in acetonitrile (553.5 μl) was added followed by addition of a solution of N-(2-mercaptoethyl)-acetamide (11.05 mg) in acetonitrile (99.45 μl) at -15° C. The mixture was allowed to stand overnight at -15° C. The resulting solution was diluted with ethyl acetate (34 ml) and washed with dilute aqueous sodium chloride and saturated aqueous sodium chloride. After drying over magnesium sulfate, the ethyl acetate extract was filtered and evaporated in vacuo. The residual oil (76.4 mg) was chromatographed on silica gel (1.5 g) eluting with a mixture of methylene chloride and acetone (20:1 to 2:1) to give 4-nitrobenzyl(5R,6S)-3-(2-acetamido-ethylthio)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-7-oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylate (54.0 mg) as an amorphous solid.
Reaction SMILES: [Br:1][CH2:2][C@@:3]([OH:8])([CH3:7])[C:4](O)=[O:5].CC(N(C)C)=O.S(Cl)(Cl)=O.[C:19]([C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=1[CH3:28])#[N:20]>C1COCC1>[Br:1][CH2:2][C@@:3]([OH:8])([CH3:7])[C:4]([NH:25][C:24]1[CH:26]=[CH:27][C:21]([C:19]#[N:20])=[C:22]([CH3:28])[CH:23]=1)=[O:5]
Reactant: Cc1cc(N)ccc1C#N
Reactant: C[C@](O)(CBr)C(=O)O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: Cc1cc(NC(=O)[C@@](C)(O)CBr)ccc1C#N
Temperature: 0 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
(2R)-3-Bromo-2-hydroxy-2-methylpropionic acid (1.52 g, 8.3 mmol) was dissolved in 35 ml of dry THF and 0.5 ml of dry DMA was added. Solution was cooled to 0° C. and thionyl chloride (0.8 ml; 10.8 mmol) was added dropwise. The solution was allowed to heat up to room temperature and stirred for 2 hours at room temperature. 4-Cyano-3-methylaniline (1.07 g, 8.1 mmol) was added in 5 ml of dry THF and reaction refluxed for 2 hours. THF was evaporated, the residue dissolved in 40 ml of CH2Cl2 and washed with 50 ml of 1% NaHCO3 and then with 4×25 ml of water. The organic phase was evaporated and residue was dried under reduced pressure at 40° C. overnight to give 2.24 g of crude product which was crystallized from 5 ml of toluene (75° C. then cooled to room temperature and to 0° C.), filtered and washed with 5 ml of ice cold toluene. The precipitate was dried under reduced pressure overnight at 40° C. to give 1.54 g of the product.
Reaction SMILES: O1C2C=CC=CC=2N=C1.[C:10]([C:13]1[CH:32]=[CH:31][CH:30]=[CH:29][C:14]=1[C:15]([NH:17][N:18]([C:20]1[O:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1)[CH3:19])=O)([OH:12])=[O:11].C(O)(=O)C.C(C1C=CC=CC=1C=O)(O)=O>O>[C:10]([C:13]1[CH:32]=[CH:31][CH:30]=[CH:29][C:14]=1[CH:15]=[N:17][N:18]([C:20]1[O:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1)[CH3:19])([OH:12])=[O:11]
Reactant: CN(NC(=O)c1ccccc1C(=O)O)c1nc2ccccc2o1
Agent: O=Cc1ccccc1C(=O)O
Agent: c1ccc2ocnc2c1
Solvent: CC(=O)O
Solvent: O
Product: CN(N=Cc1ccccc1C(=O)O)c1nc2ccccc2o1
Reaction time: 16 h

Procedure:
To a stirred suspension of 1.6 g. of the benzoxazole intermediate product of Example 1 in 50 ml. of glacial acetic acid is added 1.5 g. of 2-carboxybenzaldehyde. After a few minutes the mixture becomes homogeneous, then quickly thickens as a new precipitate forms. Stirring is continued for 16 hours, water is added, and the solid is filtered, washed with water and dried to give 2.5 g. of product, m.p. 253°-5°.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH:5](OCC)(OCC)OCC.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([Br:22])=[N:20][CH:21]=1.C(O)(=O)C>CO.C(Cl)Cl>[Br:22][C:19]1[CH:18]=[CH:17][C:16]([N:15]2[CH:5]=[N:3][N:2]=[N:1]2)=[CH:21][N:20]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(OCC)OCC
Reactant: Nc1ccc(Br)nc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: Brc1ccc(-n2cnnn2)cn1
Temperature: 80 °C
Reaction time: 7 h

Procedure:
Sodium azide (241.6 mg, 3.72 mmol) and triethyl orthoformate (1.0 mL, 6.01 mmol) were added to a stirred solution of 5-amino-2-bromopyridine (511.8 mg, 2.96 mmol) in acetic acid (3 mL, 52.4 mmol), and the reaction mixture was heated to 80° C. After 7 hours, the reaction mixture was cooled to room temperature before being evaporated under reduced pressure. The resulting red/brown solid was partitioned between EtOAc (50 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (2×50 mL). The organic layers were combined, washed with 1 N HCl (2×50 mL), saturated aqueous NaHCO3 (1×50 mL), and brine (1×50 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure to give an amber solid. Flash chromatography of the solid utilizing an 40 g silica RediSep Rf® column and employing a 0-2% MeOH/DCM gradient with a 2% MeOH/DCM hold afforded the title compound as a light yellow solid. LC-MS: calculated for C6H4BrN5 224.97, 226.96 observed m/e: 226.22, 228.21 (M+H)+ (Rt 0.42/2 min).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][C:14](=[O:31])[N:15]3[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([N:28]([CH3:30])[CH3:29])(=[O:27])=[O:26])=[CH:21][CH:20]=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].Cl[CH2:33][C:34]1[N:35]=[CH:36][N:37]([C:39]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:38]=1>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]([CH2:33][C:34]4[N:35]=[CH:36][N:37]([C:39]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)([C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=5)[C:52]5[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=5)[CH:38]=4)([CH2:33][C:34]4[N:35]=[CH:36][N:37]([C:39]([C:52]5[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=5)([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)[C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)[CH:38]=4)[C:14](=[O:31])[N:15]3[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([N:28]([CH3:29])[CH3:30])(=[O:27])=[O:26])=[CH:21][CH:20]=3)=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CN(C)S(=O)(=O)c1ccc(CN2C(=O)Cc3ccc(-c4ccc(C#N)cc4)cc32)cc1
Reactant: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1ccc(CN2C(=O)C(Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)(Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)c3ccc(-c4ccc(C#N)cc4)cc32)cc1
Reaction time: 8 h
Yield: 55.6 %

Procedure:
4-[6-(4-Cyano-phenyl)-2-oxo-2,3-dihydro-indol-1-ylmethyl]-N,N-dimethyl-benzenesulfonamide (216 mg, 0.501 mmol) and 4-chloromethyl-1-trityl-1H-imidazole compound (402 mg, 1.12 mmol) were dissolved in 5 ml of anhydrous THF under an atmosphere of dry N2. To this solution was added 95% potassium hexamethyldisilylamide (KHMDS) (230 mg, 1.10 mmol) and the reaction mixture was subsequently stirred overnight. The reaction mixture was partitioned between DCM and saturated aqueous NaHCO3. The DCM layer was dried over sodium sulfate (Na2SO4), filtered and concentrated under vacuum to give a purple foam which was chromatographed on flash silica gel eluting with a gradient of chloroform (CHCl3) to CHCl3/MeOH/NH4OH (98/2/0.01) to give 300 mg of the titled compound as a pink oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[NH:12][CH:11]=[C:10](SC)[O:9]1.O.[NH2:16][NH2:17]>COC(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[NH:12][CH:11]=[C:10]([NH:16][NH2:17])[O:9]1
Reactant: CSC1=CNN(c2ccccc2N)O1
Reactant: NN
Agent: COC(C)O
Solvent: O
Product: NNC1=CNN(c2ccccc2N)O1
Temperature: 120 °C
Reaction time: 30 h
Yield: 36.9 %

Procedure:
To a solution of 2-(2-aminophenyl)-5-(methylthio)oxadiazole (1.8 g) in methoxyethanol was added 4.4 g of hydrazine hydrate and the mixture was stirred for 30 h at 120° C. The solvent and excess hydrazine were removed and the residue was purified by column chromatography on silica gel to give 613 mg of 2-(2-aminophenyl)-5-hydrazinooxadiazole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]=O)[C:5]#[N:6].[C:12]([CH2:15][C:16](=[O:18])[CH3:17])(=O)[CH3:13].[F:19][C:20]([F:32])([F:31])[C:21]1[CH:22]=[C:23]([NH:27][C:28]([NH2:30])=[O:29])[CH:24]=[CH:25][CH:26]=1>O1CCCC1>[C:16]([C:15]1[CH:10]([C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[Br:1])[NH:30][C:28](=[O:29])[N:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:31])([F:32])[F:19])[CH:22]=2)[C:12]=1[CH3:13])(=[O:18])[CH3:17]
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: N#Cc1ccc(C=O)c(Br)c1
Reactant: CC(=O)CC(C)=O
Solvent: C1CCOC1
Product: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1Br

Procedure:
3-Bromo-4-formyl-benzonitrile (intermediate 2, 1.09 g, 4.92 mmol) is stirred with acetylacetone (0.60 mL, 5.88 mmol), 3-(trifluoromethyl)phenylurea (1.00 g, 4.90 mmol) and polyphosphoric acid (3.02 g, 7.90 mmol) in tetrahydrofurane (40.0 mL) at 50° C. overnight. The reaction mixture is concentrated in vacuo, ethyl acetate and water is added and the phases are separated. The aqueous phase is extracted twice with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over MgSO4 and concentrated. Yield: 2.38 g; ESI mass spectrum: [(79Br)-M+H]+=478, [(81Br)-M+H]+=480; Retention time HPLC: 1.06 min (HPLC method Z018_S04).
Reaction SMILES: O.[OH-].[Li+].[OH:4][C:5]([C:8]1[N:9]=[C:10]([CH2:37][CH2:38][CH3:39])[N:11]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([C:33]([O:35]C)=[O:34])=[O:32])=[CH:21][CH:20]=2)[C:12]=1[C:13]([O:15]CC)=[O:14])([CH3:7])[CH3:6]>O.O1CCOCC1>[OH:4][C:5]([C:8]1[N:9]=[C:10]([CH2:37][CH2:38][CH3:39])[N:11]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([C:33]([OH:35])=[O:34])=[O:32])=[CH:21][CH:20]=2)[C:12]=1[C:13]([OH:15])=[O:14])([CH3:6])[CH3:7]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCc1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2C(=O)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.8 %

Procedure:
A solution of 247 mg of lithium hydroxide monohydrate dissolved in 3 ml of water was added to a solution of 447 mg of ethyl 4-(1-hydroxy-1-methylethyl)-1-[(2'-methoxalylbiphenyl-4-yl)methyl]-2-propylimidazole-5-carboxylate [prepared as described in step (a) above] dissolved in 5 ml of dioxane, and the resulting mixture was stirred at room temperature for 5 hours. At the end of this time, the dioxane in the reaction mixture was removed by evaporation under reduced pressure, and 5.9 ml of 1N aqueous hydrochloric acid were added to the residue. The crystals thus precipitated were collected by filtration and dried in air, to give 310 mg of the title compound, softening at 163° C. and melting at 183°-185° C.
Reaction SMILES: C1(C)C=CC(S([O:10][CH2:11][C@H:12]2[CH2:15][C@@H:14]([C:16]3[N:20]4[CH:21]=[CH:22][N:23]=[C:24]([Cl:25])[C:19]4=[CH:18][N:17]=3)[CH2:13]2)(=O)=O)=CC=1.C1(C)C=CC(S([O:36][CH2:37][C@H:38]2[CH2:41][C@H:40]([C:42]3[N:46]4[CH:47]=[CH:48][N:49]=[C:50]([Cl:51])[C:45]4=[CH:44][N:43]=3)[CH2:39]2)(=O)=O)=CC=1.[C:53]([Si:57](Cl)([CH3:59])[CH3:58])([CH3:56])([CH3:55])[CH3:54]>>[Si:57]([O:10][CH2:11][C@@H:12]1[CH2:13][C@H:14]([C:16]2[N:20]3[CH:21]=[CH:22][N:23]=[C:24]([Cl:25])[C:19]3=[CH:18][N:17]=2)[CH2:15]1)([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:59])[CH3:58].[Si:57]([O:36][CH2:37][C@H:38]1[CH2:39][C@H:40]([C:42]2[N:46]3[CH:47]=[CH:48][N:49]=[C:50]([Cl:51])[C:45]3=[CH:44][N:43]=2)[CH2:41]1)([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:59])[CH3:58]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@H](c3ncc4c(Cl)nccn43)C2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@@H](c3ncc4c(Cl)nccn43)C2)cc1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H](c2ncc3c(Cl)nccn32)C1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@H](c2ncc3c(Cl)nccn32)C1

Procedure:
cis-3-[3-(tert-Butyldimethylsilanyloxymethyl)cyclobutyl]-8-chloroimidazo[1,5-a]pyrazine and trans-3-[3-(tert-butyldimethylsilanyloxymethyl)cyclobutyl]-8-chloroimidazo[1,5-a]pyrazine were prepared according to the general procedure for the preparation for cis-3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutylmethyl toluene-4-sulfonate and trans-3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutylmethyl toluene-4-sulfonate, except tert-butylchlorodimethylsilane was used instead of p-toluenesulfonic anhydride.