Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:4]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[C:5]([N:7]([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])=[O:6].[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][N:34]=[C:35]=[O:36].CCN(C(C)C)C(C)C.C(O)C(N)(CO)CO>C(Cl)Cl>[CH:11]([N:7]([CH:8]([CH3:9])[CH3:10])[C:5]([CH:4]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH:3]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:2][NH:1][C:35]([NH:34][CH2:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[F:26])=[O:36])=[O:6])([CH3:13])[CH3:12]
Reactant: O=C=NCc1ccccc1F
Reactant: CC(C)N(C(=O)C(c1cccnc1)C(CN)c1ccccc1)C(C)C
Agent: NC(CO)(CO)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)N(C(=O)C(c1cccnc1)C(CNC(=O)NCc1ccccc1F)c1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 4-amino-N,N-diisopropyl-3-phenyl-2-(pyridin-3-yl)butanamide (0.030 g, 0.09 mmol) in dry DCM (2 mL) was added 1-fluoro-2-(isocyanatomethyl)benzene (0.028 g, 0.18 mmol), and DIPEA (0.023 mL, 0.135 mmol). The reaction mixture was agitated for 15 h at room temperature before adding PS-trisamine (0.022 g, 0.09 mmol) and agitating for 1 h at room temperature. The crude product was then filtered to remove the solid phase and concentrated. Purification of enantiomers by ChiralPak AD (n-hexanes/EtOH, 85:15) yielded (−)-1-(3-(diisopropylcarbamoyl)-2-phenyl-3-(pyridin-3-yl)propyl)-3-(2-fluorobenzyl)urea as a foamy, off-white solid. Analytical LCMS: single peak (214 nm), 2.523 min. 1H NMR (CDCl3, 300 MHz) δ 8.26 (d, J=4.5 Hz, 1H), 8.03 (s, 1H), 7.38-7.42 (m, 2H), 7.19-7.25 (m, 1H), 6.99-7.13 (m, 6H), 6.91-6.93 (m, 2H), 4.54-4.59 (m, 1.37 (d, J=6.9 Hz, 3H), 1.26 (d, J=6.9 Hz, 3H), 1.19 (d, J=6.9 Hz, 3H), 0.60 (d, J=6.3 Hz, 3H); HRMS m/z 491.2841 (C29H35FN4O2+H requires 491.2817).
Reaction SMILES: [OH-].[K+].C([O-])C.C[O:7][C:8]([C:10]1[N:11]([CH3:33])[C:12](=[O:32])[N:13]2[C:19]3[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=3[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])=[N:16][CH2:15][C:14]=12)=[O:9]>O.CO>[Cl:24][C:22]1[CH:21]=[CH:20][C:19]2[N:13]3[C:12](=[O:32])[N:11]([CH3:33])[C:10]([C:8]([OH:9])=[O:7])=[C:14]3[CH2:15][N:16]=[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])[C:18]=2[CH:23]=1
Reactant: COC(=O)c1c2n(c(=O)n1C)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: CC[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1c(C(=O)O)c2n(c1=O)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
Potassium hydroxide, 1.3 g (0.02 mole), was dissolved in 1 ml of water and added to a suspension of 4 g (0.0097 mole) of 8-chloro-6-(2-chlorophenyl)-1,2-dihydro-2-methyl-1-oxo-4H-imidazo [1,5-a] [1,4]benzodiazepin-3-carboxylic acid methyl ester ethanolate in 200 ml of methanol. The solution was refluxed under argon for 3 hrs, concentrated at reduced pressure, diluted with cold water and acidified with acetic acid to give an off-white solid. The solid was washed with water and air dried on the funnel overnight to give crude end product. Recrystallization from ethanol/methylene chloride gave white crystals with mp 265°-267° (dec).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH:14]([OH:21])[C:15]([NH:17][CH:18]1[CH2:20][CH2:19]1)=[O:16])[CH2:9][CH:10]1[CH2:13][CH2:12][CH2:11]1)(C)(C)C.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>ClCCl>[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[NH2:7][C@@H:8]([CH2:9][CH:10]1[CH2:11][CH2:12][CH2:13]1)[CH:14]([OH:21])[C:15]([NH:17][CH:18]1[CH2:20][CH2:19]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCC1)C(O)C(=O)NC1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](CC1CCC1)C(O)C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl-(2S)-1-cyclobutyl-4-(cyclopropylamino)-3-hydroxy-4-oxobutan-2-ylcarbamate (51 mg, 0.165 mmol) was dissolved in dichloromethane (3.0 mL) and trifluoroacetic acid (3.0 mL) was added. After stirring for 1 hour at room temperature, the reaction mixture was evaporated to dryness to give (3S)-3-amino-4-cyclobutyl-N-cyclopropyl-2-hydroxy-butanamide trifluoroacetic acid salt as a white solid. A solution of (2S,4R)-1-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-4-(7-methoxy-2-(1H-pyrazol-1-yl)quinolin-4-yloxy)pyrrolidine-2-carboxylic acid in dichloromethane/N,N-dimethylformamide (1:1, 6.0 mL) was added to the (3S)-3-amino-4-cyclobutyl-N-cyclopropyl-2-hydroxy-butanamide trifluoroacetic acid salt followed by O (7 azabenzotriazol 1 yl) 1,1,3,3 tetramethyl-uronium hexafluorophosphate (HATU) (75 mg, 0.198 mmol) and diisopropylethylamine (0.1 mL, 0.7 mmol). After 24 hours at room temperature, the reaction mixture was diluted with ethyl acetate and washed with 1N HCl, saturated sodium bicarbonate, and brine. The ethyl acetate layer was dried (magnesium sulfate), filtered and evaporated to dryness under reduced pressure. The crude product was then dissolved in dry dichloromethane (10.0 mL) and 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin periodinane reagent, 112 mg, 0.264 mmol) added. After stirring at room temperature for 2 hours, the reaction mixture was quenched with 0.26M sodium thiosulfate in saturated sodium bicarbonate and extracted with ethyl acetate. The combined ethyl acetate layers were then washed with saturated sodium bicarbonate and brine. Purification by preparative HPLC gave (2S,4R)-1-((S)-(3-tert-butylureido)-3,3-dimethylbutanoyl]-N-((S)-1-cyclobutyl-4-(cyclopropylamino)-3,4-dioxobutan-2-yl)-4-(7-methoxy-2-(1H-pyrazol-1-yl)-quinolin-4-yloxy)pyrrolidine-2-carboxamide in >99% purity by HPLC.
Reaction SMILES: Cl.CO[C:4]([C@@H:6]1[C@@H:10]([OH:11])[CH2:9][CH2:8][NH:7]1)=[O:5].[Cl:12][C:13]1[C:20]([CH3:21])=[C:19]([N:22]=[C:23]=[O:24])[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]>>[Cl:12][C:13]1[C:20]([CH3:21])=[C:19]([N:22]2[C:4](=[O:5])[C@H:6]3[C@@H:10]([OH:11])[CH2:9][CH2:8][N:7]3[C:23]2=[O:24])[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: Cc1c(N=C=O)ccc(C#N)c1Cl
Reactant: COC(=O)[C@H]1NCC[C@@H]1O
Agent: Cl
Product: Cc1c(N2C(=O)[C@H]3[C@@H](O)CCN3C2=O)ccc(C#N)c1Cl

Procedure:
The title compound was prepared from compound 1A and compound 23E in a manner similar to that described in Example 19. mp 237-238° C.; HPLC: 100% at 2.11 and 2.36 min (retention time) (Conditions: Phenomenex Luna C18 (4.6×50 mm); Eluted with 0% to 100% B, 4 min gradient (A=90% H2O—10% MeOH—0.1% H3PO4 and B=10% H2O—90% MeOH—0.1% H3PO4); Flow rate at 4 mL/min. UV detection at 220 nm). Chiral HPLC: retention time=15.9 min (100%); Conditions: OD (4.6×250 mm); Eluted with 20% isopropanol in hexane for 30 min at 1 mL/min, MS (ES) m/z 306 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9].COCCOC.[BH4-].[Na+].S(=O)(=O)(O)O>O>[Cl:1][C:2]1[CH:16]=[C:15]([C:17]([F:18])([F:20])[F:19])[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][OH:9]
Reactant: O=Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: OCc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
A solution of 90 parts by weight of 3-(2'-chloro-4'-trifluoromethylphenoxy)-benzaldehyde in 300 parts by volume of ethylene glycol dimethyl ether was added dropwise to a suspension of 5.7 parts by weight of sodium borohydride in 200 parts by volume of ethylene glycol dimethyl ether at 0° C. The reaction mixture was further stirred for 12 hours at room temperature, 500 parts by volume of water were added and the mixture was acidified with 10% strength sulfuric acid. It was then extracted with ether, the organic phase was dried with magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. Fractional distillation of the residue gave 80 parts by weight (89% of theory) of 3-(2'-chloro-4'-trifluoromethylphenoxy)-benzyl alcohol (compound No. 3) of boiling point 140°-145° C./0.1 bar and refractive index nD25 : 1.5330.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=[O:6].[Cl:20][C:21]1[CH:22]=[C:23]([N:28]=[C:29]=[S:30])[CH:24]=[C:25]([Cl:27])[CH:26]=1>>[Cl:20][C:21]1[CH:22]=[C:23]([NH:28][C:29](=[S:30])[NH:1][C:2]2[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=2[O:18][CH3:19])[C:5]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)=[O:6])[CH:24]=[C:25]([Cl:27])[CH:26]=1
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Reactant: COc1ccc(C(=O)Nc2ccc(F)cc2)cc1N
Product: COc1ccc(C(=O)Nc2ccc(F)cc2)cc1NC(=S)Nc1cc(Cl)cc(Cl)c1
Yield: 76.5 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-amino-N-(4-fluorophenyl)-4-methoxy-benzamide from Example 8 (0.520 g, 2.00 mmol) and 3,5-dichlorophenyl isothiocyanate (0.409 g, 2.00 mmol). Filtration afforded the product (0.71 g) in two crops; m.p. 175-178° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]2[CH:20]=1.[N:21]([O-])=O.[Na+]>C(O)(=O)C.O>[NH2:21][C:20]1[N:11]2[CH:12]=[CH:13][C:14]3[C:19]([C:10]2=[N:9][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: Cc1ccccc1-c1cn2ccc3ccccc3c2n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccccc1-c1nc2c3ccccc3ccn2c1N
Reaction time: 1 h
Yield: 79.4 %

Procedure:
In a mixture of 30 ml of acetic acid and 6 ml of water was dissolved 2.5 g of 2-(2-methylphenyl)imidazo[2,1-a]isoquinoline with ice-cooling and stirring. A solution of 3.4 g of sodium nitrite in 12 ml of water was added portionwise to this solution and then the mixture was stirred at room temperature for 1 hour. The resulting crude crystals were collected by filtration and washing. The obtained powder was suspended in a mixture of 30 ml of acetic acid and 15 ml of water. To this suspension was added portionwise 6.3 g of zinc powder. After 1 hour, the reaction mixture was filtered, the filtrate was rendered alkaline by the addition of 28% ammonia water, and extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel and recrystallized from ethyl acetate/petroleum ether to give 2.1 g of the title compound as orange needles.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([SH:14])[CH2:12][CH3:13].Cl[C:16]1[N:30]=[C:29]([Cl:31])[C:28]([F:32])=[CH:27][C:17]=1[C:18]([NH:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:19]>C1COCC1.CN(C=O)C>[Cl:31][C:29]1[C:28]([F:32])=[CH:27][C:17]([C:18]([NH:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:19])=[C:16]([S:14][CH2:11][CH2:12][CH3:13])[N:30]=1
Reactant: O=C(NC1CCCCC1)c1cc(F)c(Cl)nc1Cl
Reactant: CCCS
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCSc1nc(Cl)c(F)cc1C(=O)NC1CCCCC1
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
A solution of sodium bis(trimethylsilyl)amide (8.24 mL, 8.24 mmol) in THF (1M) was added to a stirred solution of 1-propanethiol (0.622 mL, 6.87 mmol) in DMF (30 mL) at 5° C., over a period of 3 minutes under air. The resulting suspension was stirred at 20° C. for 15 minutes. 2,6-dichloro-N-cyclohexyl-5-fluoronicotinamide (2.0 g, 6.87 mmol) in DMF (10 mL) was added at room temperature.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:32][O:33][CH2:34][CH2:35][N:36]=[N+:37]=[N-:38])[C:10]([NH:12][CH:13]2[C:30](=[O:31])[N:15]3[C:16]([C:27]([OH:29])=[O:28])=[C:17]([CH2:20][S:21][C:22]4[S:23][CH:24]=[N:25][N:26]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.[ClH:39].CO>O1CCCC1>[ClH:39].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:32][O:33][CH2:34][CH2:35][N:36]=[N+:37]=[N-:38])[C:10]([NH:12][CH:13]2[C:30](=[O:31])[N:15]3[C:16]([C:27]([OH:29])=[O:28])=[C:17]([CH2:20][S:21][C:22]4[S:23][CH:24]=[N:25][N:26]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: [N-]=[N+]=NCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: [N-]=[N+]=NCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.6 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-(2-azidoethoxyimino)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 0.9 g.), conc. hydrochloric acid (0.2 g.), methanol (10 ml.) and tetrahydrofuran (4 ml.) was stirred at room temperature for 5 hours. After concentrating the resultant solution in vacuo, the residue was pulverized with a mixture of disopropyl ether and ethyl acetate (30 ml. 5:1 v/v). The precipitates were collected by filtration, washed with diisopropyl ether and dried to give 7-[2-(2-aminothiazol-4-yl)-2-(2-azidoethoxyimino)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer, 0.8 g.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:10]C)[C:5]([O:8]C)=[CH:6][CH:7]=1.[Br:12]B(Br)Br>ClCCl>[Br:12][C:7]1[CH:6]=[C:5]([OH:8])[C:4]([OH:10])=[CH:3][C:2]=1[F:1]
Reactant: COc1ccc(F)cc1OC
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cc(F)c(Br)cc1O
Temperature: 20 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a cooled (−78° C.) solution of 4-fluoroveratrole (5.0 g, 32 mmol) in dichloromethane (106 mL) was slowly added a solution of tribromoborane in dichloromethane (1M, 96 mL, 96 mmol, 3.0 eq.). The reaction mixture was warmed to 20° C. and stirred overnight. The reaction mixture was poured into ice water, extracted with ethyl acetate (3 times). The combined organic layer was washed with an aqueous solution of sodium bicarbonate, dried over sodium sulfate and filtered. The volatiles were removed in vacuo. The brown solid was diluted with chloroform (50 mL) and dichloromethane (10 mL). A solution of bromine in carbon tetrachloride (5 ml) was slowly added. After 3 hours, the volatiles were removed in vacuo. Purification by flash chromatography afforded the title compound (6.51 g, 98%) as a brown solid
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:18][C:19]1[CH:20]=[C:21]([C@H:25]([NH2:27])[CH3:26])[CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C.C([BH3-])#N.[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C>[F:18][C:19]1[CH:20]=[C:21]([C@H:25]([NH:27][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:26])[CH:22]=[CH:23][CH:24]=1
Reactant: O=C(c1ccccc1)c1cccc([N+](=O)[O-])c1
Reactant: C[C@@H](N)c1cccc(F)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: C[C@@H](NC(c1ccccc1)c1cccc([N+](=O)[O-])c1)c1cccc(F)c1
Yield: 94 %

Procedure:
Following a procedure similar to that described in Example (1a), 1.0 g of 3-nitrophenyl phenyl ketone, 1.12 g of (R)-1-(3-fluorophenyl)ethylamine, 3.27 ml of triethylamine, 0.56 ml of titanium tetrachloride, 1.13 g of sodium cyanoborohydride and 0.37 ml of acetic acid were reacted, to obtain 1.45 g of the title compound as a yellow oil.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[NH:19]1[CH2:24][CH2:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:35][C@H:34]([CH2:36][NH:37][C:38](=[O:40])[CH3:39])[O:33][C:32]3=[O:41])=[CH:27][CH:26]=2)=[CH:21][CH2:20]1>ClCCl>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([N:19]2[CH2:24][CH2:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:35][C@H:34]([CH2:36][NH:37][C:38](=[O:40])[CH3:39])[O:33][C:32]4=[O:41])=[CH:27][CH:26]=3)=[CH:21][CH2:20]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CCNCC3)cc2)C(=O)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(S(=O)(=O)c4ccc(C)cc4)CC3)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (202 mg), followed by p-toluenesulfonyl chloride (171 mg) were added to a stirred suspension of the TFA salt of Example 2 (322 mg) in dichloromethane (10 ml). After stirring for 30 minutes at ambient temperature, the reaction mixture had become a solution and the reaction was complete. The solution was washed with 2N HCl, water, saturated NaHCO3 and saturated NaCl. The organic phase was dried over anhydrous Na2SO4 and evaporated to give a crystalline solid which was triturated with ether to give the title compound. Yield=306 mg, 87%.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][C:12]=1[C:21]1[NH:26][C:25](=[O:27])[N:24]2[C:28]([CH3:34])=[N:29][C:30]([CH2:31][CH2:32][CH3:33])=[C:23]2[N:22]=1)[CH3:9]>ClCCl>[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)(=[O:19])=[O:18])=[CH:13][C:12]=1[C:21]1[NH:26][C:25](=[O:27])[N:24]2[C:28]([CH3:34])=[N:29][C:30]([CH2:31][CH2:32][CH3:33])=[C:23]2[N:22]=1)[CH3:9]
Reactant: CN1CCNCC1
Reactant: CCCc1nc(C)n2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nc12
Solvent: ClCCl
Product: CCCc1nc(C)n2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)ccc3OCC)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
73 mg (0.73 mmol) of N-methylpiperazine are added to a solution of 100 mg (0.24 mmol) of 4-ethoxy-3-(6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo[1,5-a][1,3,5]triazin-2-yl)-benzenesulfonyl chloride (example VI) in 5 ml of dichloromethane and the reaction mixture is stirred at room temperature for 2 hours. After chromatographic purification (dichloromethane/methanol=95:5), 110 mg (95%) of 2-[2-ethoxy-5-(4-methyl-piperazine-1-sulfonyl)-phenyl]-6-methyl-8-propyl-3H-imidazo[1,5-a][1,3,5]triazin-4-one are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][C:12]([O:14]CC)=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH2:19]O.[OH-].[Na+].O>CO>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([OH:14])[O:13][N:19]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1ccc(-c2cc(O)on2)cc1

Procedure:
According to method of U.S. Pat. No. 3,781,438, 2 g of ethyl 3-(4-nitrophenyl)-3-oxopropanoate was dissolved in methanol, slightly excessive hydroxylamine hydrochloride and equivalent amount of sodium hydroxide were added, the mixture was heated to reflux. 3 hr later, the reaction was traced by Thin-Layer Chromatography, water was added to the reaction mixture, extracted with ethyl acetate, dried and concentrated to obtain 3-(4-nitrophenyl)isoxazol-5-ol as solid.
Reaction SMILES: [Na].[CH2:2]([OH:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].Cl[CH2:12][CH:13]([OH:16])[CH2:14][OH:15]>C(OCC)C>[CH2:2]([O:10][CH2:12][CH:13]([CH2:14][OH:15])[OH:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH3:12][CH2:13][O:10][CH2:2][CH3:3]
Reactant: OCC(O)CCl
Reactant: CCCCCCCCO
Agent: [Na]
Solvent: CCOCC
Product: CCCCCCCCOCC(O)CO
Temperature: 105 °C

Procedure:
23 g (1 mol) of sodium were added in portions over the course of 4 hours to 325 g (2.5 mol) of 1-octanol while stirring at 105° C. (the temperature did not rise above 120° C. during this). The mixture was stirred at 115° C. for 1 hour. Subsequently, 110.5 g (1 mol) of 3-chloro-propane-1,2-diol were added over the course of 2 hours, and the mixture was stirred at 120° C. for 3 hours. After cooling, the mixture was taken up in 400 ml of diethyl ether and extracted 3× with a total of 700 ml of water. The ethereal phase was dried over sodium sulphate and concentrated. The residue was distilled in vacuo.
Reaction SMILES: [N:1]1([C:5]2[C:10]3=[C:11]([C:15]4[CH:16]=[N:17][N:18]([CH3:21])[C:19]=4Br)[N:12]=[C:13]([CH3:14])[N:9]3[N:8]=[CH:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:24]=[C:25]([F:33])[C:26]([Sn](C)(C)C)=[N:27][CH:28]=1>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:1]1([C:5]2[C:10]3=[C:11]([C:15]4[CH:16]=[N:17][N:18]([CH3:21])[C:19]=4[C:26]4[C:25]([F:33])=[CH:24][C:23]([Cl:22])=[CH:28][N:27]=4)[N:12]=[C:13]([CH3:14])[N:9]3[N:8]=[CH:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C[Sn](C)(C)c1ncc(Cl)cc1F
Reactant: Cc1nc(-c2cnn(C)c2Br)c2c(N3CCC3)ncnn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1nc(-c2cnn(C)c2-c2ncc(Cl)cc2F)c2c(N3CCC3)ncnn12
Temperature: 120 °C

Procedure:
4-(Azetidin-1-yl)-5-(5-bromo-1-methyl-1H-pyrazol-4-yl)-7-methylimidazo[5,1-f][1,2,4]triazine (35 mg, 0.10 mmol) and 5-chloro-3-fluoro-2-(trimethylstannyl)pyridine (59.5 mg, 0.202 mmol) were combined in toluene (1 mL) in a sealable tube and treated with dichlorobis(triphenylphosphine)palladium(II) (99%, 3.50 mg, 0.0050 mmol). The tube was sealed, and the reaction mixture was heated at 120° C. for 24 hours. The reaction was cooled, filtered through Celite and the pad was washed with ethyl acetate. After removal of solvent from the filtrate under reduced pressure, the residue was purified via silica gel chromatography (Eluant: 1% methanol in ethyl acetate) to provide the product as a solid. Yield: 20 mg, 0.050 mmol, 50%. LCMS m/z 399.1 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.21-2.30 (m, 2H), 2.59 (s, 3H), 3.86-4.14 (br m, 4H), 3.98 (s, 3H), 7.40 (dd, J=9.0, 2.0 Hz, 1H), 7.72 (s, 1H), 7.80 (s, 1H), 8.51-8.53 (m, 1H).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:13]([NH:15][C@H:16]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:1][C@@H:2]([C:13]([NH:15][C@H:16]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Reaction time: 2 h
Yield: 101.8 %

Procedure:
To a solution of 2.95 gm of BOC-D-Trp-Lys(CBZ)-OtBu (4.7 mmol) in 200 mL of methylene chloride was added 10 mL of trifluoroacetic acid. The reaction (see Scheme 1A, for reaction of 3→2) was stirred for 2 hr, and the solvent was rapidly removed under reduced pressure at less than 35 C. The oil was partitioned between 300 mL of methylene chloride and 100 mL of 50% saturated aqueous sodium bicarbonate solution. The layers were separated, the organic layer was washed with 100 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent removed under reduced pressure to yield 2.50 gm (100%) of D-Trp-Lys(CBZ)-OtBu.
Reaction SMILES: [N+:1]([C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][C:7]([OH:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2].N[CH2:17][CH2:18][CH2:19][OH:20]>O>[OH:20][CH2:19][CH2:18][CH2:17][NH:10][C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]([O:14][CH3:15])=[C:7]([OH:13])[CH:8]=1
Reactant: NCCCO
Reactant: COc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1O
Solvent: O
Product: COc1cc([N+](=O)[O-])c(NCCCO)cc1O

Procedure:
A mixture consisting of 0.2 mol (42.8 g) of 4,5-dinitro-2-methoxyphenol, prepared in Example 2, 0.6 mol (45.7 g) of 3-amino-1-propanol and 30 ml of water is heated at the refluxing temperature of water for 3 h 30 min.