Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([F:18])[CH:7]=1.[C:19]([CH2:23][CH2:24][C:25](Cl)=[O:26])([O:21][CH3:22])=[O:20]>ClCCl>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:25](=[O:26])[CH2:24][CH2:23][C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=2)=[C:8]([F:18])[CH:7]=1
Reactant: COC(=O)CCC(=O)Cl
Reactant: Fc1cc(Br)ccc1-c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CCC(=O)c1ccc(-c2ccc(Br)cc2F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
To a stirred suspension of anhydrous aluminum chloride (3.35 g, 0.0251 mol) in dichloromethane (30 mL) at 5° C. under nitrogen was added dropwise a solution of 4-bromo-2-fluoro-biphenyl (2.512 g, 0.0100 mol) in dichloromethane (17 mL) followed by a solution of 3-carbomethoxypropionyl chloride (1.34 mL, 0.0109 mol) in dichloromethane (16 mL), and the mixture stirred. After 2 hours at 5° C., the mixture was allowed to warm to room temperature and stirred for 20 hours. The reaction was recooled to 5° C. and quenched by the dropwise addition of water (60 mL). The organic layer was washed with water, saturated sodium bicarbonate, brine, and dried (Na2SO4). The organics were rotary evaporated, and the residue was purified by chromatography on silica gel, eluting with chloroform to give 3.15 g of 4-(4′-bromo-2′-fluoro-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester as a pale yellow solid; mp 94-95° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]#[C:11][CH2:12][CH2:13][CH2:14]O.CS(Cl)(=O)=O.[I-:21].[Na+]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]#[C:11][CH2:12][CH2:13][CH2:14][I:21]
Reactant: [I-]
Reactant: OCCCC#Cc1cc(F)c(F)cc1F
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Product: Fc1cc(F)c(C#CCCCI)cc1F

Procedure:
Reacting 5-(2,4,5-trifluorophenyl)-4-pentyn-1-ol (Compound 43) with methanesulfonyl chloride and sodium iodide gives 5-(2,4,5-trifluorophenyl)-1-iodo-4-pentyne. Treatment of this iodide with zinc and copper cyanide, as in Example 2, gives the corresponding mixed cuprate. Addition of this cuprate to 4-[(3-oxo-4,4,4-trifluoro)-1-butynyl]-2-trimethylsilylfuran (Compound 37) and hydrogenating the adduct gives 4-[1-(2-oxo-3,3,3-trifluoro)propyl-6-(2,4,5-trifluorophenyl)]hexyl-2-trimethylsilylfuran (Compound 44). Oxidizing this furan (Compound 44) with singlet oxygen gives 4-[1-(2-oxo-3,3,3-trifluoro)propyl-6-(2,4,5-trifluorophenyl)]hexyl-5-hydroxy-2(5H)-furanone (Compound 14).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[N+:8]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)([O-:10])=[O:9].C(OC(=O)C)(=O)C.C(=O)(O)[O-].[Na+]>>[N+:8]([C:11]1[CH:18]=[CH:17][C:14](/[CH:15]=[CH:1]/[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: Cc1ccccn1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1ccc(/C=C/c2ccccn2)cc1

Procedure:
A solution of 46.5 g (0.5 mole) of 2-methylpyridine and 75.5 g (0.5 mole) of 4-nitrobenzaldehyde in about 100 g of acetic anhydride (about 1 mole) is refluxed for 6 hours, after which it is carefully poured onto ice water. The stirred mixture is neutralized with saturated, aqueous sodium bicarbonate solution. The precipitate is filtered off under suction, washed with water and recrystallized from ethanol to give 66 g (63% of theory) of reddish brown crystals of melting point 136°-139° C.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:9]3[CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27][C:10]=3[N:11]=[C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[CH:24][N:23]=[C:22]4[CH3:26])=[CH:17][CH:16]=3)[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>CO>[CH:1]1([NH:7][C:8]2[C:9]3[CH2:30][NH:29][CH2:28][CH2:27][C:10]=3[N:11]=[C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[CH:24][N:23]=[C:22]4[CH3:26])=[CH:17][CH:16]=3)[N:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(NC4CCCCC4)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Agent: Cl
Solvent: CO
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(NC4CCCCC4)n2)CNCC3)cc1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-(cyclohexylamino)-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (124 mg, 0.25 mmol) was dissolved in methanol (2 mL). Hydrochloric acid (7.48 μL, 0.25 mmol) was added and the reaction mixture was stirred at 75° C. for 1 h. The solvent was evaporated under reduced pressure and the crude N4-cyclohexyl-N2-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (93 mg, 94%) was used as such in the subsequent step. MS (ES+) m/z 404.3 (M+H)+
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([O:18][CH3:19])=[C:12]([Cl:20])[C:11]=1[C:21]1[N:26]=[C:25]2[NH:27][N:28]=[CH:29][C:24]2=[CH:23][N:22]=1>CN(C)C=O.O>[Cl:9][C:10]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([O:18][CH3:19])=[C:12]([Cl:20])[C:11]=1[C:21]1[N:26]=[C:25]2[NH:27][N:28]=[C:29]([I:1])[C:24]2=[CH:23][N:22]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1cc(OC)c(Cl)c(-c2ncc3cn[nH]c3n2)c1Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)c(Cl)c(-c2ncc3c(I)n[nH]c3n2)c1Cl
Temperature: 40 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
N-Iodosuccinimide (0.23 g, 1.0 mmol) was added to a solution of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (0.30 g) in N,N-dimethylformamide (5.0 mL). The reaction mixture was stirred at 40° C. overnight. The reaction mixture was diluted with water and quenched with aqueous Na2S2O3. The precipitates formed were filtered, washed with water, ether, and dried in vacuum to afford the desired product (0.33 g). LCMS (M+H)+=450.8/452.8.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26]OS(C)(=O)=O)=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[NH:32]1[CH2:36][CH2:35][CH2:34][C@H:33]1[CH2:37][OH:38]>CS(C)=O>[NH:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][N:32]4[CH2:36][CH2:35][CH2:34][C@H:33]4[CH2:37][OH:38])=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:12][CH2:13]1
Reactant: OC[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCOS(C)(=O)=O)ccc23)CC1
Solvent: CS(C)=O
Product: OC[C@@H]1CCCN1CCOc1ccc2c(C3CCNCC3)ncnc2c1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[7-(2-methanesulfonyloxy-ethoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester (40.6 mg, 0.09 mmol) in DMSO (0.4 mL) was added (S)-(+)-2-pyrrolidinemethanol (90.9 mg, 0.9 mmol). The mixture was stirred at 120° C. overnight and subsequently partitioned between EtOAc and water. The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was treated with 50% TFA/CH2Cl2 (8 mL) for 2 h, the solvents (TFA/CH2Cl2) were removed under reduced pressure to provide the desired product. LC-MS (ESI) calcd for C20H29N4O2 (MH+) 357.2, found 357.2.
Reaction SMILES: [CH:1]1([Li])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:12][CH2:13]Br>C1COCC1>[CH:1]1([CH:7]([CH:6]2[C:12]3[C:13](=[CH:9][CH:1]=[CH:2][CH:3]=3)[CH:4]=[CH:5]2)[CH3:8])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: [Li]C1C=Cc2ccccc21
Reactant: BrCCBr
Solvent: C1CCOC1
Product: CC(C1C=Cc2ccccc21)C1C=Cc2ccccc21
Reaction time: 4 h

Procedure:
Am. Chem. Soc., 109 (1987) 6544-6545, to J. A. Ewen et al. discloses a process similar to the one of Collins wherein, as described in the supplementary material to the article, two equivalents of indenyllithium are reacted with 1,2-dibromoethane dissolved in THF by warming the reaction mixture from −91° C. to 25° C. and stirring for 4 h. Bisindenylethane was obtained in a crude yield of 60%. The product was recrystallized from ethanol.
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[C:31]([C:33]2([OH:39])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH:30]=[C:29]([F:40])[C:28]=1[C:41]1[N:46]=[C:45]([C:47](O)=[O:48])[CH:44]=[CH:43][C:42]=1[F:50]>>[NH2:9][C@H:8]1[C@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:47](=[O:48])[C:45]2[CH:44]=[CH:43][C:42]([F:50])=[C:41]([C:28]3[C:29]([F:40])=[CH:30][C:31]([C:33]4([OH:39])[CH2:34][CH2:35][O:36][CH2:37][CH2:38]4)=[CH:32][C:27]=3[F:26])[N:46]=2)[CH2:6][CH2:7]1
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cc(C3(O)CCOCC3)cc2F)n1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2ccc(F)c(-c3c(F)cc(C4(O)CCOCC4)cc3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(2,6-difluoro-4-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)-5-fluoropicolinic acid (see US2012/225062) gave 196. 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.29 (dd, J=8.7, 4.0 Hz, 1H), 8.23-8.10 (m, 1H), 7.88 (s, 1H), 7.49-7.35 (m, 2H), 4.85-4.76 (m, 1H), 4.39-4.11 (m, 1H), 4.07-3.68 (m, 9H), 3.17-3.03 (m, 1H), 2.11-1.99 (m, 3H), 1.84-1.51 (m, 5H). LCMS (ES+) m/z 564 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:16](=[O:19])[CH2:17][CH3:18])[CH:7]=[C:8]([S:10]([F:15])([F:14])([F:13])([F:12])[F:11])[CH:9]=1)[CH3:2].[Br-:20].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.O.C(=O)([O-])O.[Na+]>C1COCC1.CC(=O)OCC>[Br:20][CH:17]([CH3:18])[C:16]([C:6]1[CH:7]=[C:8]([S:10]([F:11])([F:12])([F:13])([F:15])[F:14])[CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)=[O:19]
Reactant: CCOc1cc(C(=O)CC)cc(S(F)(F)(F)(F)F)c1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(C(=O)C(C)Br)cc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Yield: 109.8 %

Procedure:
1-[3-Ethoxy-5-(pentafluorosulfanyl)phenyl]propan-1-one (O2.064; 150 mg) was dissolved in THF (15 ml), and phenyltrimethylammonium tribromide (185 mg) was added while stirring at RT. After stirring at RT for 5 h, the mixture was admixed with water and saturated sodium hydrogencarbonate solution, and EA was added. The EA phase was removed and the alkaline water phase was extracted three times with EA. The combined organic phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by means of preparative HPLC (met. A). The product fractions, each of them clean, were combined, freed of the acetonitrile under reduced pressure, alkalized with saturated sodium hydrogencarbonate solution and extracted five times with EA. The combined organic phases were dried over magnesium sulfate and, after filtering off the desiccant, dried under reduced pressure. 120 mg of the title compound were isolated.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([CH3:12])[C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[CH:3]=1.C([Sn](CCCC)(CCCC)CCCC)C=C.[Cl-].[Li+].C1(C)C=CC=CC=1.[CH3:38][CH2:39][O:40]C(C)=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][C:10]1[C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[CH:3]=[C:2]([CH2:38][CH:39]=[O:40])[CH:11]=1
Reactant: CCOC(C)=O
Reactant: Cc1cc(Br)cc2c1C(=O)OC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Cc1cc(CC=O)cc2c1C(=O)OC2

Procedure:
To a flask charged with 5-bromo-7-methyl-2-benzofuran-1(3H)-one (27 mg, 0.12 mmol) and a stir bar was added allyl tri-n-butyltin (79 mg, 0.24 mmol), lithium chloride (15 mg, 0.36 mmol), palladium tetrakis (28 mg, 0.024 mmol), and toluene (4 mL). The reaction was sealed with a condensor, purged three times with nitrogen, and heated to reflux for 16 hours. LC showed good reaction at that point. The reaction was diluted with EtOAc, adsorbed onto silica gel, and purified by flash chromatography. Removal of solvent gave rise to (7-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde as a light yellow oil. LC/MS: (IE, m/z) (M+1)+=189.2.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].[CH2:12]([O:14][C:15](=[O:23])[CH:16]=[CH:17]N1CCCC1)[CH3:13].C(N(CC)CC)C>C(OCC)C>[CH2:12]([O:14][C:15]([C:16]1[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH3:10])=[N:2][O:1][CH:17]=1)=[O:23])[CH3:13]
Reactant: CCOC(=O)C=CN1CCCC1
Reactant: Cc1ccccc1C(Cl)=NO
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1conc1-c1ccccc1C
Yield: 47 %

Procedure:
To a stirred solution of N-hydroxy-2-methylbenzenecarboximidoyl chloride (2.07 g, 12.2 mmol, 1.0 equiv) in diethyl ether (15 mL) was added a solution of 3-pyrrolidin-1-yl-acrylic acid ethyl ester (prepared according to the procedure described in U.S. Pat. No. 4,187,099) (2.06 g, 12.2 mmol, 1.0 equiv) and triethylamine (1.48 g, 12.2 mmol, 1.0 equiv) in diethyl ether (30 mL) dropwise over 15 minutes. The resultant mixture was stirred at ambient temperature for 16 hours, partitioned between water and diethyl ether and separated. The aqueous phase was extracted with diethyl ether (2×), and the combined ethereal extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by flash column chromatography on silica gel (gradient: 0 to 20% ethyl acetate in cyclohexane) gave 1.32 g (47%) of 3-o-tolyl-isoxazole-4-carboxylic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ: 9.02 (s, 1H), 7.39-7.34 (m, 1H), 7.32-7.24 (m, 3H), 4.19 (q, 2H), 2.23 (s, 3H), 1.17 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=[C:6]([Br:9])[C:7]=1[CH3:8].[H-].[Na+].Br[CH2:15][CH3:16]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][O:11][CH2:15][CH3:16])[CH:5]=[C:6]([Br:9])[C:7]=1[CH3:8]
Reactant: Cc1c(Br)cc(CO)cc1Br
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCc1cc(Br)c(C)c(Br)c1
Temperature: 70 °C
Yield: 49.7 %

Procedure:
A mixture of (3,5-dibromo-4-methyl-phenyl)-methanol (4 g, 14.288 mmol), 60% NaH (690 mg, 28.75 mmol) and THF (72 mL) was heated to 70° C. in a sealed tube for 15 minutes. The reaction was cooled, bromoethane (3.2 mL, 42.86 mmol) was added and the reaction continued heating at 70° C. for 6 h. The reaction was cooled, poured onto water, extracted with EtOAc (×3). The organics were washed with water, brine and dried (Na2SO4). Chromatography (Hexanes/EtOAc) afforded 1,3-dibromo-5-ethoxymethyl-2-methyl-benzene (2.187 g) as a colourless oil. 1H NMR (400 MHz, d6-DMSO) δ: 1.15 (t, 3H), 2.48 (s, 3H), 3.46 (q, 2H), 4.41 (s, 2H), 7.57 (s, 2H) ppm.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH:13]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH2:8][CH2:7]1)=O)C.[OH-].[K+].O>C(O)C>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH:13]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH2:12][N:9]2[CH2:10][CH2:11][NH:6][CH2:7][CH2:8]2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)N1CCN(CC(c2ccc(F)cc2)N2CCN(C)CC2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN1CCN(C(CN2CCNCC2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Yield: 98.8 %

Procedure:
1.25 g of 1-Ethoxycarbonyl-4-[2-(4-fluorophenyl)-2-(4-methylpiperazino)ethyl]piperazine was dissolved in 2 ml of ethanol, and 1.3 g of potassium hydroxide was added, followed by reflux with heating for an hour. The reaction solution was cooled to room temperature and, after addition of 2 ml of water, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure to give 1.0 g of a crude 1-[2-(4-fluorophenyl)-2-(4-methyl-piperazino)ethyl]piperazine.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9]([C:11]1[N:12]=[C:13]([CH3:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)=[O:10].[S:24]1[C:28]2[CH:29]=[CH:30][C:31]([C:33](O)=[O:34])=[CH:32][C:27]=2[N:26]=[N:25]1>>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:4]2[C@H:3]([CH2:2][NH:1][C:33]([C:31]3[CH:30]=[CH:29][C:28]4[S:24][N:25]=[N:26][C:27]=4[CH:32]=3)=[O:34])[CH2:8][C@H:7]3[C@@H:5]2[CH2:6]3)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1
Reactant: O=C(O)c1ccc2snnc2c1
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3ccc4snnc4c3)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [(1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl]-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone with benzo[1,2,3]thiadiazole-5-carboxylic acid. LC-MS (basic): tR=0.88 min; [M+H]+=494.1.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:5]=[CH:6][NH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:3].ClC(Cl)C(O)=O.[CH:21]([O:23][CH2:24][CH3:25])=[CH2:22].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:3][CH:2]([C:4]1[N:5]=[CH:6][N:7]([CH:21]([O:23][CH2:24][CH3:25])[CH3:22])[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:1]
Reactant: C=COCC
Reactant: CC(C)c1nc[nH]c1-c1ccccc1
Agent: O=C(O)C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCOC(C)n1cnc(C(C)C)c1-c1ccccc1
Temperature: 25 °C
Yield: 97.1 %

Procedure:
A mixture of 10.0 g (0.055 mole) of 4-(1-methylethyl)-5-phenyl-1H-imidazole, 7.61 g (0.06 mole) of dichloroacetic acid and 29.3 g (0.41 mole) of ethyl vinyl ether in 585 ml of toluene was heated at reflux for 3.5 hours. The reaction mixture was cooled to room temperature and was then stirred overnight with 170 ml of 25% aqueous sodium hydroxide. The organic layer was separated. The aqueous was extracted with ether (2×). The organic fractions were combined, washed with brine and dried over anhydrous potassium carbonate. Removal of the solvent under vacuum afforded 13.8 g of an oil, which was used in the subsequent reaction without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH:11]2[C:16](=O)[CH2:15][CH2:14][S:13][CH2:12]2)=O)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH:32][C:33]([NH2:35])=[NH:34])[CH:23]=[CH:24][C:25]=1[N:26]1[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CCO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:11]3[CH2:12][S:13][CH2:14][CH2:15][C:16]=3[N:35]=[C:33]([NH:32][C:22]3[CH:23]=[CH:24][C:25]([N:26]4[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]4)=[C:20]([O:19][CH3:18])[CH:21]=3)[N:34]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCSCC1C(=O)Cc1ccc(F)cc1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: COc1cc(Nc2nc3c(c(Cc4ccc(F)cc4)n2)CSCC3)ccc1-n1cnc(C)c1
Temperature: 60 °C

Procedure:
3-(2-(4-Fluorophenyl)acetyl)dihydro-2H-thiopyran-4(3H)-one (200 mg, 0.79 mmol), 1-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)guanidine (194 mg, 0.79 mmol) and potassium carbonate (200 mg, 1.45 mmol) was slurrified in EtOH (5 mL) and heated to 60° C. for 16 h. DCM and water were added to the cooled reaction mixture. The organic phase was separated and dried with Mg2SO4 and then the solvent was evaporated. The crude product was used as such in next step. MS (ES+) m/z 462.2 (M+H)+
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-:10])=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:5]=1)([O-])=O>[Pd].O.C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][N+:7]([O-:10])=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:5]=1
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(-c2ccccn2)c1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: Nc1cc[n+]([O-])c(-c2ccccn2)c1
Yield: 84.6 %

Procedure:
A suspension of 2.6 grams (0.012 mole) of 4-nitro-2-(2-pyridinyl)pyridine-N oxide and 0.42 gram of 10% palladium on charcoal in 10 ml of water and 200 ml of ethanol was hydrogenated using a Parr hydrogenator. Upon completion of hydrogenation the reaction mixture was purged with nitrogen gas for one hour, then concentrated under reduced pressure to a residual solid. The solid was triturated with 200 ml of water. The mixture was filtered and the filter cake washed with water. The combined filtrate and wash were concentrated under reduced pressure to a residue. The residue was taken up in 30 ml of ethanol and concentrated under reduced pressure. This procedure was repeated three additional times to remove residual water. The residue was dried under reduced pressure at 60° C. to yield 1.9 grams of 4-amino-2-(2-pyridinyl)pyridine-N oxide as a solid. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:21]=[C:20]([Br:22])[C:19]([Cl:23])=[CH:18][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:10][CH2:11][C:5]2=[N:4][N:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[Br:22][C:20]1[C:19]([Cl:23])=[CH:18][C:8]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:10][CH2:11][C:5]3[N:6]([C:2]([N:28]4[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]4)=[N:3][N:4]=3)[C:7]=2[CH:21]=1
Reactant: Clc1cc2c(cc1Br)-n1c(Br)nnc1CN=C2c1ccccn1
Reactant: CN1CCNCC1
Product: CN1CCN(c2nnc3n2-c2cc(Br)c(Cl)cc2C(c2ccccn2)=NC3)CC1

Procedure:
In the manner given in Example 1, 1,9-dibromo-8-chloro-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with 1-methylpiperazine to give 9-bromo-8-chloro-1-(4-methylpiperazino)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11]1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC1CCCC1)c1ccc(N)cc1
Yield: 53.2 %

Procedure:
A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid ethyl ester (7.37 g, 25.3 mmol) in ethyl acetate (316 mL) was treated with 10% palladium on activated carbon (500 g). The reaction mixture was shaken under 60 psi of hydrogen gas at 25° C. for 18 h. The catalyst was then filtered off through a pad of celite and was washed with ethyl acetate. The filtrate was concentrated in vacuo to give 2-(4-amino-phenyl)-3-cyclopentyl-propionic acid ethyl ester (3.52 g, 53.3%) as a yellow oil: EI-HRMS m/e calcd for C16H23NO2 (M+) 261.1727, found 261.1727.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.BrC[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[N:30]=1>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH2:21][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[N:30]=1
Reactant: Clc1cccc(CBr)n1
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Product: Clc1cccc(CSc2c(Cl)ccc3c2CCNCC3)n1

Procedure:
Use a method similar to the Preparation 177, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 2-bromomethyl-6-chloropyridine hydrochloride to give, after deprotection by a method similar to the General Procedure 1-4, the title compound as an off-white solid. MS (APCI+) m/z: 339 (M+H)+.