Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1>C(O)C>[OH:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([O-:14])=[O:13])=[CH:10][CH:9]=1.[NH2+:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: O=C(O)c1ccc(O)cc1
Solvent: CCO
Product: C1CC[NH2+]CC1
Product: O=C([O-])c1ccc(O)cc1

Procedure:
Piperidine (0.85 g; 10 mmol) was added dropwise to a solution of 4-hydroxybenzoic acid (1.38 g; 10 mmol) in ethanol (10 cm3). The resulted in the precipitation of a white solid. The product was collected by filtration and recrystallized from water to produce translucent, colourless crystals. Found: C, 64.6%; H, 7.6%; N, 6.2%. Calculated for C12H17NO3 ; C, 64.55%; H, 7.69%; N, 6.24%. M.pt. 197°-199° C.
Reaction SMILES: [C:1]1([CH2:11][NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:16](Cl)[N:15]=1.C(N(CC)CC)C>C(#N)C>[Cl:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:16]([NH:12][CH2:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[N:15]=1
Reactant: NCc1cccc2ccccc12
Reactant: Clc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Clc1nc(NCc2cccc3ccccc23)c2ncn(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 64 h
Yield: 97.4 %

Procedure:
1-Naphthylmethanamine (5.4 g, 19.7 mmol) was added to a stirred solution of 2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (3.5 g, 22.3 mmol) (Preparation 19) and triethylamine (4 g, 39.6 mmol) in acetonitrile (150 ml) at room temperature. The reaction mixture was stirred at room temperature for 64 hours. The solvent was removed under reduced pressure, ethyl acetate (100 ml) was added and then the solvent was removed under reduced pressure again. The residue was purified by column chromatography on silica gel eluting with pentane: ethyl acetate (1:1 by volume) increasing in polarity to neat ethyl acetate. The solvent was removed under reduced pressure to give the title compound (7.56 g) as a solid.
Reaction SMILES: [F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C@H:8]([CH3:18])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH:24]=[N:25][C:26]([CH3:32])=[N:27]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C@H:8]([CH3:18])[CH2:9][C@@:10]([C:13]([F:14])([F:15])[F:16])([OH:17])[CH:11]=[N:21][C:22]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:23]=2[CH:24]=[N:25][C:26]([CH3:32])=[N:27]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ncc2c(N)cccc2n1
Reactant: COc1c(F)cccc1[C@H](C)C[C@@](O)(C=O)C(F)(F)F
Agent: [Ti+4]
Agent: CC[O-]
Product: COc1c(F)cccc1[C@H](C)C[C@@](O)(C=Nc1cccc2nc(C)ncc12)C(F)(F)F

Procedure:
In the same way as in Example 1, 135 mg (0.46 mmol) of (2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal, 100 mg (0.63 mmol) of 5-amino-2-methylquinazoline and 0.23 ml of titanium tetraethoxide are reacted to give (2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-1-[(2-methylquinazolin-5-yl)imino]-2-(trifluoromethyl)pentan-2-ol. 260 mg of resultant crude imine are cyclized, in the same way as in Example 1, at −30° C. using 5 ml (5 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 0-75%) yields 56 mg of product.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)(N1C=CN=C1)=[O:2].Cl.[OH:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CCOCC.N1(CCN)C[CH2:35][CH2:34][CH2:33][CH2:32]1>O1CCCC1>[CH:20]1([CH2:19][CH2:18][N:17]([CH2:16][CH2:15][OH:14])[C:1]([NH:8][CH2:12][CH2:11][N:10]2[CH2:9][CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:2])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCCN1CCCCC1
Reactant: OCCNCCC1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(NCCN1CCCCC1)N(CCO)CCC1CCCCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1,1′-Carbonyldiimidazole (740 mg) was dissolved in a solution of 2-(1-piperidyl) ethylamine (0.50 ml) in anhydrous tetrahydrofuran (18 ml) under the nitrogen gas atmosphere and then the mixture was stirred at room temperature for 20 minutes. N-(2-Hydroxyethyl)-2-cyclohexylethylamine hydrochloride (875 mg) was added to the reaction solution and the mixture was refluxed with heating for 3 hours. Ether was added to the reaction solution with ice cooling, the resulting mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated sodium chloride aqueous solution in this order, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting oily product was purified through the silica gel column chromatography to give the title compound (Compound 1-1, 1.01 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:16]C)=[C:4]([C:8]2[O:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)[Br:19]>ClCCl>[BrH:19].[NH2:1][C:2]1[C:3]([OH:16])=[C:4]([C:8]2[O:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: BrB(Br)Br
Reactant: COc1c(N)cccc1-c1ccc(C(=O)O)o1
Solvent: ClCCl
Product: Br
Product: Nc1cccc(-c2ccc(C(=O)O)o2)c1O
Reaction time: 1 h
Yield: 47.2 %

Procedure:
5-(3-Amino-2-methoxy-phenyl)-furan-2-carboxylic acid 4f (2.79 g, 11.97 mmol) was dissolved in 25 mL of dichloromethane followed by dropwise addition of boron tribromide (23.9 mL, 2.0 M). The reaction mixture was reacted at room temperature for 1 hour. The mixture was concentrated under reduced pressure after 5 mL of methanol was added. The residue was diluted with 100 mL of ethyl acetate and stirred for 1 hour. Then the mixture was filtered and the filter cake was dried to obtain the title compound 5-(3-amino-2-hydroxy-phenyl)-furan-2-carboxylic acid hydrobromide 4g (1.24 g, yield 47.2%) as a yellow solid.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Si:5]([O:12][CH2:13][CH:14]=O)([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].[BH4-].[Na+].Cl[CH:19](Cl)[CH3:20]>C(O)(=O)C>[Si:5]([O:12][CH2:13][CH2:14][NH:4][CH:1]1[CH2:20][CH2:19][CH2:2][CH2:3]1)([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: NC1CC1
Reactant: CC(Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OCCNC1CCCC1
Reaction time: 24 h
Yield: 37.48 %

Procedure:
To a stirred solution of cyclopropylamine (1 g, 13.15 mmol) in dichlorethane (20 mL) were added 2-(tert-butyl-dimethylsilanyloxy)acetaldehyde (2.3 mg, 2.30 mmol) and acetic acid (0.08 mL, 0.29 mmol) at 0° C. Stirring was continued for 24 h at room temperature and NaBH4 (995 mg, 26.29 mmol) was added portion-wise at 0° C. The reaction mixture was further stirred for 2 h at room temperature, quenched with water and extracted with dichloromethane (3×30 mL). The organic part was dried and concentrated to yield a crude product which was purified by Combi-Flash column (eluted at 10-20% ethyl acetate in hexane) to get [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopentylamine (8e) (1.2 g, 37.48%) as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:15]1[CH2:14][CH:13]1[CH2:11][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1
Reactant: ClCC1CO1
Reactant: NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(OCC2CO2)cc1
Temperature: 70 °C
Reaction time: 18 h
Yield: 28.4 %

Procedure:
To a sealed tube was added 4-hydroxybenzamide (200 mg, 1.458 mmol), epichlorohydrin (135 mg, 1.458 mmol) and potassium carbonate (403 mg, 2.916 mmol) in 7 mL of dry DMF. The reaction mixture was stirred at 70° C. for 18 h. The reaction mixture was filtered and concentrated. The residue was purified by flash chromatography, eluting with 0-5% 2M NH3 in MeOH/CH2Cl2. The product fractions were collected and concentrated to afford 80 mg of 4-oxiranylmethoxy-benzamide as a white solid.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][Si](C(C)(C)C)(C)C)[CH2:9][C@H:8]1[CH:20]=[C:21]([CH3:25])[C:22](=[O:24])[CH3:23])=[O:6])[CH:2]=[CH2:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.O>O1CCCC1>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH:20]=[C:21]([CH3:25])[C:22](=[O:24])[CH3:23])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=C(C)C(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1C=C(C)C(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-4-t-butyldimethylsilyloxy-2-(2-methyl-3-oxo-1-butenyl)-pyrrolidine (9.9 g) in tetrahydrofuran (99 ml) was added lM solution of tetrabutylammonium fluoride in tetrahydrofuran (32.3 ml) at 0° C. After stirring at room temperature for 1 hour, the reaction mixture was poured into a mixture of ethyl acetate (200 ml) and water (100 ml). The aqueous layer was separated and extracted with ethyl acetate. The combined organic layer was washed twice with 1N hydrochloric acid (25 ml) and then with saturated aqueous sodium bicarbonate, water and brine successively, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (100 ml) eluting with a mixture of n-hexane and ethyl acetate (1:1-1:2 V/V) to give (2S,4R)-1-allyloxycarbonyl-4-hydroxy-2-(2-methyl-3-oxo-1-butenyl)pyrrolidine (5.65 g).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])I.S[CH:16]([OH:18])[CH3:17].C([O-])=O.[Na+].O.O.O.O.O.O.O.[S:30]([O-])([O-])=O.[Na+].[Na+].C(OC(C)C)(C)C>CN(C=O)C.O>[F:7][C:5]([F:8])([S:30][CH2:17][CH2:16][OH:18])[C:4]([F:10])([F:9])[C:3]([F:12])([F:11])[C:2]([F:14])([F:13])[F:1]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Reactant: O=S([O-])[O-]
Reactant: CC(O)S
Agent: O=C[O-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: O
Solvent: CN(C)C=O
Product: OCCSC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 23 °C

Procedure:
1,1,1,2,2,3,3,4,4-nonafluoro-4-iodobutane (138.4 g (400 mmol)) was dissolved in a mixture liquid of DMF (400 ml) and water (80 ml), and mercaptoethanol (32.2 g (400 mmol)) was added. Further, sodium formate (27.2 g (400 mmol)), sodium sulfite heptahydrate (100.9 g (400 mmol)) were added, and stirred at room temperature (23° C.) for one night. Water (1 L) and isopropyl ether (1 L) were added to the reaction liquid, which was separated. A water layer was further extracted with isopropyl ether (500 ml×2). The organic layer washed with 10% hydrochloric acid (500 ml), water (500 ml) and a saturated saline solution (500 ml), dried over anhydrous magnesium sulfate and filtered. The solvent was distilled off to give 2-(perfluorobutylthio)ethanol. Then, p-toluene sulfonic acid monohydrate (2.5 g (13.1 mmol)) was added to a solution of 2-(perfluorobutylthio)ethanol (50 g (equivalent to 158 mmol)) and 2,3-dichloropropionic acid (22.5 g (157 mmol)) in cyclohexane (500 ml), and was subjected to dehydration condensation reaction (bath temperature: 90° C.) for one night by using a Dean-Stark method. The reaction liquid was filtered with celite. An organic layer washed with water three times and with saturated saline solution, and dried over anhydrous magnesium sulfate. The filtration and concentration under reduced pressure gave crude 2-(perfluorobutylthio)ethyl 2,3-dichloropropionate (63.8 g). Yield: 96.5%.
Reaction SMILES: C(O)C.[CH3:4][N:5]([CH3:24])[CH:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[C:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(O)[CH2:7]1.N.[Na]>O1CCCC1>[CH3:4][N:5]([CH3:24])[CH:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7]1
Reactant: CN(C)C1CCc2ccccc2C(O)(c2ccccc2)C1
Agent: N
Agent: [Na]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(C)C1CCc2ccccc2C(c2ccccc2)C1
Temperature: -40 °C
Reaction time: 0.33 h

Procedure:
12.4 ml of ethanol and then a solution of 12 g of 7-dimethylamino-5ξ-phenyl-5ξ-hydroxy-6,7,8,9-tetrahydro [5H] benzocycloheptene in 200 ml of tetrahydrofuran were added to 600 ml of condensed ammonia and then 2.46 of sodium were added at -40° C. The mixture was stirred at -40° C for 20 minutes and the ammonia and tetrahydrofuran were evaporated. The residue was dissolved in ethyl acetate and the solution was washed with water, dried and evaporated to dryness. The residue was chromatographed over silica gel and eluted with a 9-1-1 cyclohexane-ethyl acetate-triethylamine mixture to obtain 3.2 g of isomer A (equatorial 5-H) and 6.5 g of isomer B (axial 5-H) of 7-dimethylamino-5-phenyl-6,7,8,9-tetrahydro [5H] benzocycloheptene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH:10]=[CH:9][C:5]2=[N+:6]([O-])[CH:7]=1.C[CH2:14][N:15](CC)CC.C[Si](C#N)(C)C>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH:10]=[CH:9][C:5]2=[N:6][C:7]=1[C:14]#[N:15]
Reactant: Cn1ccc2c1cc(Br)c[n+]2[O-]
Reactant: CCN(CC)CC
Agent: C[Si](C)(C)C#N
Solvent: ClCCCl
Product: Cn1ccc2nc(C#N)c(Br)cc21
Temperature: 80 °C
Reaction time: 5 h
Yield: 75.6 %

Procedure:
To a stirred mixture of 6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridine 4-oxide (3.8 g 14 mmol), Et3N (19.51 mL, 140 mmol) and DCE (20 mL) was added trimethylsilyl cyanide (9.38 mL, 70.0 mmol). The reaction mixture was stirred at 80° C. for 5 h, subsequently concentrated in vacuo, and purified by silica gel chromatography eluting with EtOAc/DCM (1:1) to give the title compound as an off-white solid (2.50 g, 76%, 2 steps). ESI-MS m/z [M+H]+ calc'd for C9H6BrN3, 236, 238; found 236, 238.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[N:11]=[C:12]=[O:13].CCCCC(C(O[Sn](O[C:34](C(CCCC)CC)=[O:35])(CCCC)CCCC)=O)CC.[CH3:43][N:44]([CH3:49])[C:45]([S:47][NH2:48])=[S:46].CO>C1(C)C=CC=CC=1>[CH3:43][N:44]([CH3:49])[C:45]([S:47][NH:48][C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:11][C:12]([O:35][CH3:34])=[O:13])[CH:4]=1)=[O:10])=[S:46]
Reactant: CCCCC(CC)C(=O)O[Sn](CCCC)(CCCC)OC(=O)C(CC)CCCC
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Reactant: CN(C)C(=S)SN
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)Nc1cc(NC(=O)NSC(=S)N(C)C)ccc1C
Temperature: 75 °C

Procedure:
Toluene-2,4-diisocyanate (17.9 g, 0.10 mole) and dibutyltin di-2-ethylhexanoate (0.20 g) were dissolved in toluene (100 ml). The solution was heated to 75° C., and then a solution of S-(di-methylthiocarbamyl)sulfenamide (13.6 g, 0.10 mole) in toluene (200 ml) was added slowly, with constant stirring, over a period of 45 minutes. When the addition was complete, the mixture was maintained at 70°-80° C. and stirred for an additional hour. Then anhydrous methanol (15 ml) was added. The slurry was stirred and maintained at 70°-80° C. for one more hour. The slurry was cooled to room temperature and filtered. The white powdery product was dried at 60° C. Yield 30.5 g, 89.2%, mp 180°-185° C. IR and NMR spectra were consistent with the assigned structure.
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[NH2:15][CH2:16][CH:17]1[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]1>ClCCl>[C:8]([NH:15][CH2:16][CH:17]1[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]1)(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CC(CN)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCC1CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (0.76 ml, 5.45 mmol) and acetic anhydride (0.43 ml, 4.56 mmol) were added to an ice-cooled solution of tert-butyl 3-(aminomethyl)-1-azetidinecarboxylate (J. Med. Chem. 2001; 44(1); 94) (850 mg, 4.56 mmol) in dichloromethane (50 ml), and the reaction stirred for 30 minutes. The solution was washed with water (50 ml), brine (50 ml), dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using ethyl acetate as eluant to afford the title compound as a yellow oil.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][CH2:13][N:14]([CH3:57])[C:15](=[O:56])[C:16]1[CH:55]=[CH:54][CH:53]=[C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:24][C:23]=2[C:34]2[CH:39]=[C:38]([C:40](=[O:52])[NH:41][C@@H:42]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH2:45][CH2:44][CH2:43]3)[CH:37]=[CH:36][N:35]=2)=[O:20])[CH:17]=1.C(N(CC)CC)C>C(Cl)Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH3:57][N:14]([CH2:13][CH:12]=[O:11])[C:15](=[O:56])[C:16]1[CH:55]=[CH:54][CH:53]=[C:18]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:24][C:23]=2[C:34]2[CH:39]=[C:38]([C:40](=[O:52])[NH:41][C@@H:42]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH2:45][CH2:44][CH2:43]3)[CH:37]=[CH:36][N:35]=2)=[O:20])[CH:17]=1
Reactant: CN(CCO)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN(CC=O)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of DMSO (2.07 mmol, 162 mg) in DCM (1.6 mL) at −78° C. was added a solution of oxalyl chloride (1.04 mmol, 131 mg) in DCM (0.2 mL). The mixture was stirred at −78° C. for 15 minutes. Then a solution of (S)—N1-(2-hydroxyethyl)-N1-methyl-N3-(4-(piperidin-1-yl)-2-(4-((1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)phenyl)isophthalamide Example 115 (0.69 mmol, 435 mg) in DCM (0.5 mL) was added. The mixture was stirred at −78° C. for 3 h. Triethylamine (0.5 mL) was added. The mixture was slowly warmed to room temperature. The mixture was diluted with aqueous 10% citric acid and extracted with DCM (3×). The combined organic layers was washed with water (1×), dried, concentrated to give a yellow solid which was used without purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH2:9])=[O:8].[CH:10](=O)[CH2:11][CH2:12][CH2:13][CH3:14].C([BH3-])#N.[Na+]>CO>[CH2:10]([NH:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH2:9])=[O:8])[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: NC(=O)c1[nH]cnc1N
Reactant: CCCCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCCCNc1nc[nH]c1C(N)=O
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
4-Amino-1H-imidazole-5-carboxamide (13.0 g, 0.104 mol) and valeraldehyde (11 mL, 0.10 mol) were mixed in methanol (200 mL). After being stirred for 30 min, sodium cyanoborohydride (6.5 g, 0.10 mol) was added to the solution and stirring was continued overnight. The reaction mixture was concentrated under reduced pressure. The remaining residue was taken up in EtOAc and the resulting solution was washed with saturated NaHCO3. The aqueous layer was extracted with EtOAc three times. The combined organic layers were dried (MgSO4) and concentrated. The residue was purified by flash chromatography (DCM to 5% MeOH/DCM) to give the desired product (12.9 g, 63.1%). LCMS calculated for C9H16N4O (M+H): 197.1. found: 180.1 (M+H—NH3).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([NH:18][NH2:19])=[O:17])=[C:5]2[C@@H:4]2[CH2:20][CH2:21][N:3]12.[Cl:22][CH2:23][C:24](=N)OCC>CN(C)C=O.C(O)C>[Cl:22][CH2:23][C:24]1[O:17][C:16]([C:15]2[N:14]=[CH:13][N:6]3[C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[C:2](=[O:1])[N:3]4[CH2:21][CH2:20][C@H:4]4[C:5]=23)=[N:18][N:19]=1
Reactant: NNC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1ccccc1-2
Reactant: CCOC(=N)CCl
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C1c2ccccc2-n2cnc(-c3nnc(CCl)o3)c2[C@@H]2CCN12
Yield: 54.1 %

Procedure:
A solution of 5 g (17.64 mmol) of (S)-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid hydrazide and 3.06 g (19.41 mmol) of ethyl chloroacetimidate in 40 ml of dimethylformamide and 10 ml of ethanol was stirred at 90° for 12 hours. The solvent was evaporated and the residue was partitioned between methylene chloride and water. The aqueous phase was back-washed once with methylene chloride. The organic phases were dried with magnesium sulfate, filtered and evaporated. Chromatography of the residue (silica gel, methylene chloride/methanol 93:3) yielded 3.26 g (55%) of (S)-1-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one as a colourless foam, RF=0.5 (methylene chloride/methanol 10:1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[N+:9]([CH2:12][CH3:13])([O-:11])=[O:10].[OH-].[Na+]>CCO.O>[N+:9]([CH:12]([CH3:13])[CH:7]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[OH:8])([O-:11])=[O:10]
Reactant: O=Cc1ccncc1
Reactant: CC[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C(O)c1ccncc1)[N+](=O)[O-]

Procedure:
A solution of 1.0 eq. of 4-pyridinecarboxaldehyde (63, Aldrich, cat. no. P6,240-2) and 1.5 eq of nitroethane (Aldrich, cat. no. 22,787-0) in absolute EtOH was stirred at 0° C. as a solution of 2.0 eq. of NaOH in water was added. After a time sufficient for reaction completion, the reaction mixture was concentrated by rotary evaporation and neutralized (pH 7-8) with conc. HCl. A white precipitate formed. The mixture was extracted with EtOAc. The organic layer was dried over MgSO4, filtered and the solvent removed by rotary evaporation. The material was purified by flash chromatography on silica gel using a mixture of MeOH—CH2Cl2 as eluant to afford 64 as a mixture of diastereomers.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([O:33][CH3:34])[CH:30]=[N:31][CH:32]=1>>[CH3:34][O:33][C:29]1[CH:28]=[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:32]=[N:31][CH:30]=1
Reactant: COc1cncc(Br)c1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: COc1cncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1)(355 mg, 1.0 mmol) and commercially available 5-bromo-3-methoxypyridine (169 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (210 mg, 45%). MS (ISP) 463.2[(M+H)+]; mp 232-234° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:15]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:9]=[CH:8]1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH4-].[Na+]>C(Cl)Cl>[CH2:16]([N:12]1[CH2:13][CH2:14][C:15]2[N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH:8]=[N:9][C:10]=2[CH2:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(-n2cnc3cnccc32)nc1
Reactant: BrCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(CN2CCc3c(ncn3-c3ccccn3)C2)cc1
Reaction time: 4 h
Yield: 0.1 %

Procedure:
To a solution of Intermediate 3 (0.20 g, 1.02 mmol) in DCM (25 mL) was added benzyl bromide (0.12 g, 1.02 mmol). The reaction was let stir for 4 h then concentrated. The resulting solid was dissolved in MeOH (10 mL) and NaBH4 (0.05 g, 1.4 mmol) was added slowly. After 5 h, the reaction was quenched with a small amount of water and concentrated. Chromatography of the resulting residue (SiO2; MeOH(NH3):DCM) gave the title compound (0.20 mg, 68%). 1H NMR (500 MHz, CDCl3) δ 8.76-8.66 (m, 1H), 8.55-8.39 (m, 2H), 8.14-8.03 (m, 1H), 7.32 (ddt, J=22.0, 11.6, 7.5 Hz, 6H), 3.89 (s, 1H), 3.78 (d, J=5.4 Hz, 2H), 3.63 (s, 1H), 2.99 (t, J=5.5 Hz, 1H), 2.83 (tt, J=26.6, 5.6 Hz, 3H). MS (ESI): mass calculated for C18H18N4, 290.2. m/z found 291.2 [M+H]+.