Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:14]([C:15]3[CH:19]=[CH:18][O:17][N:16]=3)[N:4]2[N:3]=1.[CH2:20]([N:23]1[CH:27]=[N:26][C:25]([CH2:28][OH:29])=[N:24]1)[CH2:21][CH3:22]>>[O:17]1[CH:18]=[CH:19][C:15]([C:14]2[N:4]3[N:3]=[C:2]([O:29][CH2:28][C:25]4[N:26]=[CH:27][N:23]([CH2:20][CH2:21][CH3:22])[N:24]=4)[C:11]4[C:6]([C:5]3=[N:12][N:13]=2)=[CH:7][CH:8]=[CH:9][CH:10]=4)=[N:16]1
Reactant: Clc1nn2c(-c3ccon3)nnc2c2ccccc12
Reactant: CCCn1cnc(CO)n1
Product: CCCn1cnc(COc2nn3c(-c4ccon4)nnc3c3ccccc23)n1

Procedure:
The title-compound was prepared from 6-chloro-3-(isoxazol-3-yl)-1,2,4-triazolo[3,4-a]phthalazine (described in Example 34 part b) and 1-propyl-3-hydroxymethyl-1,2,4-triazole prepared as described in WO-A-9804559 using the procedure given for Example 71, 1H NMR (360 MHz, CDCl3) δ 0.95 (3H, t, J=7.4 Hz, CH3), 1.89-1.99 (2H, m, CH2), 4.15 (2H, t, J=7.0 Hz, CH2), 5.73 (2H, s, CH2), 7.40 (1H, d, J=1.7 Hz, Ar—H), 7.80 (1H, t, J=7.2 Hz, Ar—H), 7.96 (1H, t, J=6.9 Hz, Ar—H), 8.09 (1H, s, Ar—H), 8.28 (1H, d, J=7.9 Hz, Ar—H), 8.70 (1H, s, Ar—H), 8.74 (1H, d, J=7.7 Hz, Ar—H); MS tES+) m/e 377 1MH]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:12](=O)[CH:13]([OH:21])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][NH:11][CH2:12][CH:13]([OH:21])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(CCNC(=O)C(O)c2cccc(Cl)c2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CCNCC(O)c2cccc(Cl)c2)cc1

Procedure:
A solution of N-[2-(4-methoxyphenyl)ethyl]-2-hydroxy-1-oxo-2-(3-chlorophenyl)ethanamine (2.8 g) in dry tetrahydrofuran (20 ml) was added slowly to a refluxing suspension of lithium aluminium hydride (1.36 g) in tetrahydrofuran (30 ml) at reflux and then heated under reflux for 24 hours. After careful addition of water (1.4 ml), aqueous sodium hydroxide (10%; 1.4 ml) and water (2.8 ml), filtration and evaporation of the filtrate gave the crude product. Recrystallisation from ethyl acetate-hexane gave N-[2-(4-methoxyphenyl)-ethyl]-2-hydroxy-2-(3-chlorophenyl)ethanamine, mp 101°-3° C.
Reaction SMILES: [S:1]1[C:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])([CH:4]=[CH2:5])[CH2:2]1>C1C=CC=CC=1>[CH2:6]([C:3]1[CH2:2][S:1][CH2:5][CH:4]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: C=CC1(CCCCCC)CS1
Solvent: c1ccccc1
Product: CCCCCCC1=CCSC1
Yield: 90.5 %

Procedure:
A solution of 1,2-epithio-2-hexyl-3-butene (40 mg, 0.24 mmol) and Cu(hfacac)2 (1.2 mg, 2.4 μmol) in benzene (1 mL) was heated at 80° C. for 0.5 h in a pressure tube. Concentration of the solvent in vacuo afforded a residue, which was purified by column chromatography (n-pentane) to give 3-Hexyl-2,5-dihydrothiophene (37 mg, 93%) as a colorless oil.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16](=O)OC(C)(C)C)[CH2:11]2)=[N:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:16][NH:15][C@@H:12]1[CH2:13][CH2:14][N:10]([C:4]2[C:5]3[CH:9]=[CH:8][NH:7][C:6]=3[N:1]=[CH:2][N:3]=2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Temperature: 65 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
Under N2, to a solution of (R)-tert-butyl 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-ylcarbamate (380 mg, 1.34 mmol) in anhydrous THF (10 mL) was slowly added Lithium aluminium hydride (143 mg, 3.76 mmol) at 0° C. After the completion of the addition, the reaction mixture was stirred at 65° C. for 2 hours. The reaction mixture was then cooled to 0° C., quenched with aqueous NaOH (15%), and filtrated to remove the solid. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC to give the title compound (178 mg, 66% yield). MS (m/z): 218 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[CH:17]=[N:16][N:15]([CH3:18])[C:14]=3[C:19]([OH:21])=O)=[O:11])[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[CH3:29][NH:30][CH:31]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32]1>>[CH3:18][N:15]1[C:14]([C:19](=[O:21])[N:30]([CH3:29])[CH:31]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32]2)=[C:13]([NH:12][C:10]([C:8]2[C:7]([NH:22][C:23]3[CH:28]=[N:27][CH:26]=[N:25][CH:24]=3)=[N:6][CH:5]=[C:4]([CH:1]3[CH2:2][CH2:3]3)[N:9]=2)=[O:11])[CH:17]=[N:16]1
Reactant: CNC1CCN(C)C1
Reactant: Cn1ncc(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)c1C(=O)O
Product: CN1CCC(N(C)C(=O)c2c(NC(=O)c3nc(C4CC4)cnc3Nc3cncnc3)cnn2C)C1

Procedure:
The product was obtained starting from 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-2-methyl-2H-pyrazole-3-carboxylic acid (25 mg, 66 μmol; example 236, step 3) and N,1-dimethyl-pyrrolidin-3-ylamine (10 mg, 85 μmol) according to the method described in example 64, step 6 after purification by preparative HPLC using an acetonitrile/water gradient as yellow solid (12 mg, 35%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:5]1([CH:3]=[O:2])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][N:6]=1
Reactant: COC(=O)c1nccc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1nccc2ccccc12
Yield: 63.6 %

Procedure:
1-Isoquinolinecarboxaldehyde (7.3 g, 64%) was prepared from 1-isoquinolinecarboxylic acid methyl ester (13.6 g, 0.073 mol) and 1M LAH (36.6 ml in THF) in 300 ml of dry THF (J. Org. Chem., vol 28, p 1898, 1963) to afford 7.3 g (64%) of 1-isoquinolinecarboxaldehyde.
Reaction SMILES: Cl.[CH2:2]([O:4][NH2:5])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[C:22]([CH:23]=O)=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]>CO>[Cl:12][C:13]1[C:22]([CH:23]=[N:5][O:4][CH2:2][CH3:3])=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C=O)c1Cl
Reactant: CCON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCON=Cc1c(S(C)(=O)=O)ccc(C(=O)OC)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
1.90 g (0.0195 mol) of O-ethylhydroxylamine hydrochloride and 1.35 g (0.0097 mol) of finely powdered potassium carbonate were stirred for 1 hour at room temperature in 60 ml of dry methanol, and 4.90 g (0.0177 mol) of methyl 2-chloro-3-formyl-4-methylsulfonylbenzoate were then added. After stirring for 8 hours at room temperature, the solvent was removed, the residue was taken up in ethyl acetate and the organic phase was washed with water until neutral, dried and concentrated under reduced pressure. 5.00 g of methyl 2-chloro-3-ethoxyiminomethyl-4-methylsulfonylbenzoate were obtained. (Yield 88%).
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[CH3:14])[CH:2]([CH3:4])[CH3:3].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH2:37]([C:39]1[C:44]([C:45](=[N:47]O)[NH2:46])=[CH:43][CH:42]=[C:41]([CH2:49][O:50][Si](C(C)C)(C(C)C)C(C)C)[N:40]=1)[CH3:38].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>>[CH2:37]([C:39]1[N:40]=[C:41]([CH2:49][OH:50])[CH:42]=[CH:43][C:44]=1[C:45]1[N:47]=[C:9]([C:8]2[CH:12]=[CH:13][C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])=[C:6]([CH3:14])[CH:7]=2)[O:11][N:46]=1)[CH3:38]
Reactant: Cc1cc(C(=O)O)ccc1CC(C)C
Reactant: CCc1nc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc1C(N)=NO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCc1nc(CO)ccc1-c1noc(-c2ccc(CC(C)C)c(C)c2)n1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 12 (12a) using 4-isobutyl-3-methylbenzoic acid (92 mg, 0.48 mmol) that was obtained in Example 27 (27d), 1-hydroxybenzotriazole (69 mg, 0.51 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (97 mg, 0.51 mmol), 2-ethyl-N′-hydroxy-6-{[(triisopropylsilyl)oxy]methyl}pyridine-3-carboximidamide (0.16 g, 0.46 mmol) that was obtained in Example 25 (25b), and a 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.92 ml, 0.92 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:3) as the eluent to afford the title compound (0.15 g) in a yield of 93% as a white crystalline solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2([C:12]([F:15])([F:14])[F:13])[N:11]=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K]>CN(C)C=O>[F:13][C:12]([F:15])([F:14])[C:9]1([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH2:2][N:20]2[C:16](=[O:26])[C:17]3[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:19]2=[O:21])[NH:11][NH:10]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: FC(F)(F)C1(c2cccc(CBr)c2)N=N1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1cccc(C2(C(F)(F)F)NN2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
A mixture of 3-(3-bromomethyl-phenyl)-3-trifluoromethyl-3H-diazirine, (140 mg, 0.5 mmol) and potassium phthalimide (95 mg, 0.5 mmol) in dimethylformamide (1.5 mL) was stirred at room temperature for 3 hrs. Dimethylformamide was removed in vacuo. The residue was extracted with CH2Cl2, washed with water, then dried (Na2SO4), filtered, and concentrated. The resulting residue was purified by column chromatography (SiO2, 1:1 CH2Cl2/pentane) to provide 140 mg (Yield 82%) of the title compound as a solid; 1H NMR (300 MHz, CDCl3) δ ppm: 4.80 (2H, s) 7.09-7.21 (2H, m) 7.32 (1H, t, J=7.9 Hz) 7.41-7.49 (2H, m) 7.66-7.71 (2H, m) 7.81-7.85 (2H, m); LC/MS m/z 346 (M+H).
Reaction SMILES: I[CH2:2]I.[Br:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH:14]=[CH2:15])[CH:6]=1.Cl>C(Cl)Cl>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH:14]2[CH2:2][CH2:15]2)[CH:6]=1
Reactant: C=COc1cc(Br)ccc1OC
Reactant: ICI
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(Br)cc1OC1CC1
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 69.5 %

Procedure:
Into a 25 mL flame-dried flask were added diethylzinc (8.75 mL, 1 N solution in hexanes). The solution was cooled to −20° C. and a solution of trichloroacetic acid (1.43 g, 8.75 mmol, dissolved in 2 mL of CH2Cl2 was added dropwise over 10 min, then the solution was stirred an additional 20 min. A solution of diiodomethane (2.38 g, 8.89 mmol) in 1 mL CH2Cl2 was then added dropwise and the solution was stirred an additional 20 minutes. A solution of 4-bromo-1-methoxy-2-vinyloxy-benzene (1.029 g, 4.365 mmol, dissolved in 900 uL CH2Cl2) was then added and the reaction mixture was stirred for 8 h at room temperature. The reaction mixture was poured onto a 100 mL 1 N aqueous HCl solution containing some ice, then extracted 3× with EtOAc. The combined organic phase was washed with 1 N aqueous NaHCO3, brine, then dried (MgSO4), filtered and concentrated. Purification by flash column on silica gel (0-100% Hexanes/EtOAc gradient) to afford titled compound as a colorless crystalline solid (738 mg, 67%). 1H NMR (DMSO-d6) 7.33 (s, 1H), 7.06 (d, J=8.4, 1H), 6.90 (d, J=8.4, 1H), 3.84 (m, 1H), 3.70 (s, 3H), 0.75 (m, 2H), 0.64 (m, 2H). LC/MS (Method B) 3.64 min, [M+1]+ 243/245.
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:10][C:9]([CH2:19][OH:20])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.O>CS(C)=O>[C:1]1([N:7]2[C:11]([NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:10][C:9]([CH:19]=[O:20])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1cc(Nc2ccccc2)n(-c2ccccc2)n1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1cc(Nc2ccccc2)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.4 %

Procedure:
[1-Phenyl-5-(phenylamino)-1H-pyrazol-3-yl]methanol (318 mg) and triethylamine (1 mL) were dissolved in dimethyl sulfoxide (5 mL), and sulfur trioxide•pyridine complex (535 mg) was added at room temperature. After stirring at room temperature for 18 hr, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=7:1→3:1) to give the title compound as a pale-yellow powder (yield 238 mg, yield 81%).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[C:8](=[O:43])[NH:9][C:10](=[O:42])[N:11]([CH:41]=1)[C@@H:12]1[O:40][C@H:16]([CH2:17][O:18][C:19]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C@@H:14]([OH:15])[CH2:13]1)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:6]([C:7]1[C:8](=[O:43])[NH:9][C:10](=[O:42])[N:11]([CH:41]=1)[C@@H:12]1[O:40][C@H:16]([CH2:17][O:18][C:19]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[C@@H:14]([OH:15])[CH2:13]1)#[CH:5]
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C#C[Si](C)(C)C)c(=O)[nH]c3=O)C[C@@H]2O)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cn([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccc(OC)cc3)O2)c(=O)[nH]c1=O
Reaction time: 7 h

Procedure:
1.40 g of 2′-deoxy-5-[(trimethylsilyl)ethynyl]-5′-O-(4-methoxytrityl)-uridine (2.35 mmole) prepared in 1-2) was dissolved in 20 ml of THF, and then 0.95 ml TBAF (1.4 eq) was added thereto. After 7 hours, the reaction was terminated, THF was removed using a rotary evaporator, and the resulting residue was subjected to column chromatography (silica gel 60, 230-400 meshes, Merck) to obtain the title compound as a solid. The chromatography was conducted using a mixture of CH2Cl2 and methanol as an eluting solution whose mix ratio was gradually varied from 100:1 to 50:1 (v/v).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C:11](=[CH:15][CH2:16][OH:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(Cl)Cl>CCCCCC.[O-2].[O-2].[Mn+4]>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C:11](=[CH:15][CH:16]=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(=CCO)CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCCC(=CC=O)CC1
Reaction time: 18 h
Yield: 55.5 %

Procedure:
Manganese dioxide (507 g) was added to a solution of 61 g (0.25 mol) of 4-(2-hydroxyethylidene)azepane-1-carboxylic acid t-butyl ester obtained in the above 2) in a mixture of hexane (1865 ml)-chloroform (624 mL) and stirred for 18 hours. After the reaction was completed, insoluble materials were filtered off through Celite and the filtrate was concentrated under a reduced pressure to obtain 33.2 g (yield 55%) of 4-(2-oxoethylidene)azepane-1-carboxylic acid t-butyl ester (VII-17, 125, 126). Its physical property is shown below.
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:16][CH:17]1[C:28](=[O:29])[N:19]2[CH:20]([C:25]([OH:27])=[O:26])[CH:21]([OH:24])[CH2:22][S:23][C@H:18]12>C(OCC)(=O)C.CS(C)=O>[NH2:16][CH:17]1[C:28](=[O:29])[N:19]2[CH:20]([C:25]([O:27][CH:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:26])[CH:21]([OH:24])[CH2:22][S:23][C@H:18]12
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(O)CS[C@H]12
Temperature: 25 °C
Reaction time: 32 h
Yield: 68.1 %

Procedure:
A solution of dipheyldiazomethane (1.7 mol) in ethyl acetate (2.13 l) was added to a mixture of 7-amino-3-hydroxycepham-4-carboxylic acid (186 g) in dimethyl sulfoxide (1.5 l). The mixture was stirred at room temperature for 32 hours and filtered. To the filtrate was added water and the mixture was extracted with ethyl acetate. The extract was washed three times with water, dried over magnesium sulfate and filtered, and the filtrate was evaporated in vacuo. The residue was tritulated with diisopropyl ether to give benzhydryl 7-amino-3-hydroxycepham-4-carboxylate (223 g) as powder.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=1)=[O:11].Br[C:25]1[C:30]([F:31])=[CH:29][C:28]([C:32]([F:35])([F:34])[F:33])=[CH:27][N:26]=1>>[F:31][C:30]1[C:25]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[C:17]([N:18]3[N:22]=[CH:21][CH:20]=[N:19]3)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=2)=[O:11])=[N:26][CH:27]=[C:28]([C:32]([F:34])([F:33])[F:35])[CH:29]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Reactant: Fc1cc(C(F)(F)F)cnc1Br
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(C(F)(F)F)cc2F)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone and 2-bromo-3-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 478 [M+1]+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH2:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][NH2:17]>>[NH2:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][NH:17][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(-c2ccncc2)n1
Reactant: NC[C@@H](N)Cc1ccccc1
Product: N[C@H](CNc1cccc(-c2ccncc2)n1)Cc1ccccc1
Temperature: 190 °C

Procedure:
A neat mixture of 6-bromo-[2,4′]bipyridine (2.35 gm, 10 mmole) and (S)-2-amino-3-phenylpropylamine (3 gm, 20 mmole) was heated to 190° C. for 4 hr. The reaction was cooled to rt and purified (SiO2, CH2Cl2/MeOH/NH4OH: 100/11/8) to give the step 1 compound. (This reaction provides major products wherein the less hindered amine functionality displaces the bromide,when the nucleophile is an alkyldiamine) MS (m/z): Calcd. C19H20N4 (M+): 304, found (M+H)+: 305.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:16][O:17][CH2:18][C:19]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)[CH:7]=1.FC(F)(F)C(O)=O.C(Cl)Cl>>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[N:15])=[CH:12][CH:13]=2)[CH:5]=[C:4]([CH2:16][O:17][CH2:18][C:19]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc(-c3ccc(C#N)cc3)c2)(c2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(-c2cc(Br)cc(COCC3(c4ccccc4)CCNCC3)c2)cc1

Procedure:
tert-Butyl 4-(((5-bromo-4′-cyanobiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (24.3 mg, 0.04 mmol) was treated with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvent was evaporated and the compound purified by column chromatography (10% ammonia in methanol/methylene chloride) to afford 13.2 mg (72%). 1H-NMR (CDCl3, 500 MHz) δ 7.71-7.73 (m, 2H), 7.31-7.37 (m, 5H), 7.28 (s, 1H), 7.20-7.22 (m, 2H), 4.38 (s, 2H), 3.44 (s, 2H), 2.91-2.94 (m, 2H), 2.74-2.78 (m, 2H), 2.16-2.20 (m, 2H), 1.89-1.93 (m, 2H). Mass spec.: 463.09 (MH)+. Accurate mass spec.: m/z 463.1205 [MH]+, Δ=1.0 ppm.
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.[CH:7]1[C:17]2[CH:16]=[CH:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[C:12](=[CH:22][C:23]([OH:25])=[O:24])[C:11]=2[CH:10]=[CH:9][CH:8]=1>C1C=CC=CC=1>[CH3:1][O:24][C:23](=[O:25])[CH:22]=[C:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:17]=2[CH:16]=[CH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]1=2
Reactant: O=C(O)C=C1c2ccccc2C=Cc2ccccc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Product: COC(=O)C=C1c2ccccc2C=Cc2ccccc21

Procedure:
Oxalyl chloride (2.665 g., 1.79 mL, 0.021 mole) is added to a suspension of (5H dibenzo[a,d]cyclohepten-5-ylidene)acetic acid (5.000 g., 0.020 mole) in dry benzene (70 mL). An exothermic reaction occurs and the solid gradually dissolves. After solution is complete, the mixture is refluxed for one hour, then concentrated in vacuo to give an amber oil which crystallizes on storage at ambient temperature. Absolute methanol (75 mL) is added to the solid acid chloride. The mixture is stirred magnetically until complete solution is obtained, then refluxed for 45 minutes. The solvent is evaporated in vacuo to give a crystalline solid. The yield of crude ester melting at 83.5°-84.5° C. (uncorr.) is 5.210 g. (99.31%). Recrystallization of this material from methanol affords colorless rods melting at 86.0°-86.5° C. (uncorr.) in a yield of 3.508 g. (66.86%).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:16])([F:15])[F:14].CN(C1C=CC=CC=1)[CH:19]=[O:20].S(=O)(=O)(O)O>O1CCCC1>[Cl:6][C:7]1[C:8]([C:13]([F:14])([F:15])[F:16])=[CH:9][CH:10]=[CH:11][C:12]=1[CH:19]=[O:20]
Reactant: CN(C=O)c1ccccc1
Reactant: FC(F)(F)c1ccccc1Cl
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cccc(C(F)(F)F)c1Cl
Reaction time: 1.5 h

Procedure:
Butyl lithium (36.4 ml of 1.6M in hexane) was added to a stirred solution at -65° of 1-chloro-2-(trifluoromethyl)-benzene (10 g) in dry tetrahydrofuran (100 ml) over 20 mins. After stirring for 1.5 hours at -65°, a solution of N-methyl-N-phenylformamide (6.85 ml) in tetrahydrofuran (30 ml) was added over 1 hour. The reaction mixture was left at this temperature for 1.5 hours and then allowed to reach room temperature. It was then poured onto 10% sulphuric acid, extracted with ether and the organic extract was washed with brine, dried (Na2SO4) and the solvent removed in vacuo. The residue was distilled (20 mmHg, oven temperature 100°-125°); the distillate was cooled, filtered and the solid washed with petroleum ether (60°-80°) to give the desired aldehyde (3.5 g) as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:3]=1[CH2:4][N:5]1[C:17]2[CH:16]=[N:15][C:14]([C:18](OC)=[O:19])=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:3]=1[CH2:4][N:5]1[C:17]2[CH:16]=[N:15][C:14]([CH2:18][OH:19])=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: COC(=O)c1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cc2c3ccccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Yield: 90.8 %

Procedure:
A mixture of methyl 9-(2,5-dichlorobenzyl)-9H-β-carboline-3-carboxylate (13.05 g, 0.0339 mol), and sodium borohydride (3 g, 0.079 mol) was stirred and refluxed in anhydrous ethanol (200 mL) for 15 h. The ethanol was evaporated, and the residue partitioned between 10% aqueous Na2CO3 (100 mL) and methylene chloride (100 mL). The organic phase was dried over MgSO4, evaporated, and the residue crystallized from ether, affording the title product as an ivory-colored solid (11 g, 91%).