Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([C:12]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=O)[CH:6]=[CH:5][C:4]=2[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[N:14]1([CH2:12][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[CH2:3][C@@H:2]([NH2:1])[CH2:11][CH2:10]3)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: N[C@H]1CCc2cc(C(=O)N3CCCC3)ccc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N[C@H]1CCc2cc(CN3CCCC3)ccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of ((S)-6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)pyrrolidin-1-ylmethanone (0.49 g) in THF (5 ml) was added dropwise to a suspension of lithium aluminum hydride (0.60 g) in THF (10 ml). The mixture was stirred at RT for one hour. Water (0.6 ml) was cautiously added dropwise, followed by sodium hydroxide solution (16%; 2 ml) and water again (2 ml). The precipitate which formed was filtered off and the filtrate was concentrated. The residue was taken up in hydrochloric acid (1N) and the solution was washed with diethyl ether. The aqueous phase was basified with concentrated sodium hydroxide solution and extracted three times with dichloromethane (DCM). The combined organic phases were dried over magnesium sulfate and concentrated. The product was thus obtained with the molecular weight of 230.36 (C15H22N2); MS (ESI): 231 (M+H+).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].CC(C)([O-])C.[K+].Cl[C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:20]([F:26])=[CH:19][C:18]=1[N+:27]([O-:29])=[O:28].[NH4+].[Cl-]>CC(N(C)C)=O.O1CCOCC1>[F:26][C:20]1[CH:21]=[C:22]([N+:23]([O-:25])=[O:24])[C:17]([CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[C:18]([N+:27]([O-:29])=[O:28])[CH:19]=1
Reactant: O=[N+]([O-])c1cc(F)cc([N+](=O)[O-])c1Cl
Reactant: COC(=O)CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CC(=O)N(C)C
Product: COC(=O)C(C(=O)OC)c1c([N+](=O)[O-])cc(F)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
To a solution of dimethyl malonate (16.3 mL, 143 mmol) in DMA (100 mL) at ambient temperature was added potassium tert-butoxide (15.3 g, 136 mmol). The reaction mixture was heated to 70° C. for 30 min, then removed from the oil bath. A solution of 2-chloro-5-fluoro-1,3-dinitrobenzene (14.3 g, 64.9 mmol) in dioxane (70 mL) was added drop wise over 30 min. The reaction mixture was stirred for 10 min, then cooled and poured onto saturated aqueous NH4Cl (500 mL). The aqueous layer was extracted with EtOAc (250 mL) and Et2O (2×250 mL). The combined organic extracts were washed with H2O (100 mL), dried over Na2SO4, and concentrated in vacuo to give the title compound, which was used without further purification. MS: m/z=317 (M+1).
Reaction SMILES: [C-:1]1([CH2:6][CH2:7][OH:8])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.[Fe+2:14].N1C=CC=CC=1.[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23]>CCOCC>[C:21]([O:8][CH2:7][CH2:6][C-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1)(=[O:25])[C:22]([CH3:24])=[CH2:23].[CH-:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.[Fe+2:14]
Reactant: OCC[c-]1cccc1
Reactant: C=C(C)C(=O)Cl
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: CCOCC
Solvent: c1ccncc1
Product: C=C(C)C(=O)OCC[c-]1cccc1
Reaction time: 4 h

Procedure:
2-ferrocenylethyl alcohol obtained from Example 1 (0.8 g) is dissolved in 300 ml anhydrous ether and 0.4 g of pyridine are added. The solution of 0.5 ml methacryloyl chloride in 30 ml ether is added dropwise and the reaction is continued for four hours. The precipitate is removed by filtration and the ether solutions are combined, washed with 5% sodium bicarbonate, 5% hydrochloric acid, sodium bicarbonate again and dried. The ether is evaporated, leaving a brown viscous oil that is further purified by chromatography over silica (ether as eluent).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16].Cl>O.O1CCOCC1>[CH3:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([C:15]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:16])[C:1]=1[OH:4]
Reactant: O=C([O-])[O-]
Reactant: NCCCCCCCC(=O)O
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(C(=O)NCCCCCCCC(=O)O)c1O
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A 50% (by weight) solution of potassium carbonate (24 mL, 36 g, 0.127 mol, 1.23 eq), 8-aminocaprylic acid (16.44 g, 0.103 mol, 1.00 eq), and water (20 mL) were added to a 250 mL round bottom flask equipped with a magnetic stir bar and an addition funnel. The white cloudy mixture was treated with a solution of oligo(3-methylsalicylate) (15.90 g, 0.114 mmol 1.11 eq) and dioxane (90 mL), added over five minutes. The addition funnel was replaced with a condenser, and the reaction mixture was heated to 90 degrees C. for 4 hours (at which time the reaction was determined to have finished, by HPLC). The clear orange reaction mixture was cooled to 40 degrees C. and acidified to pH=1 with 3% (by vol.) aqueous hydrochloric acid. All the dioxane and some of the water were stripped (60 degrees C., 50 mm). The water layer from the resulting two-phase mixture was decanted while still warm. The orange oil was crystallized from 65% ethanol-water to give a tan solid upon cooling to -10 degrees C. The solid was recrystallized from 50 mL of 65% ethanol-water. The off-white solid was washed with hot water (30 mL) to remove most of the remaining salicylic acid. The solid was recovered by filtration and was dried over 6 hours in a 50 degrees C. vacuum oven. The N-(3-methylsalicyloyl)-8-aminocaprylic acid was isolated as a light tan solid (12.32 g, 41%).
Reaction SMILES: Br.Br[C:3]1[S:7][C:6]([NH2:8])=[N:5][CH:4]=1.[CH2:9]([O:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:20])[CH:14]=1)[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH2:9]([O:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([O:19][C:3]2[S:7][C:6]([NH2:8])=[N:5][CH:4]=2)=[C:15]([F:20])[CH:14]=1)[CH3:10]
Reactant: Nc1ncc(Br)s1
Reactant: CCOC(=O)c1ccc(O)c(F)c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(Oc2cnc(N)s2)c(F)c1
Temperature: 25 °C
Yield: 40.3 %

Procedure:
To a solution of 5-Bromothiazole-2-amine hydrobromide (1.55 g, 5.97 mmol) in acetone (100 mL) was added 3-fluoro-4-hydroxy benzoic acid ethyl ester (1.1 g, 5.97 mmol) and cesium carbonate (3.89 g, 11.94 mmol) under argon atmosphere and refluxed for 5 hrs. The reaction mixture was cooled to room temperature and filtered; the filtrate was concentrated under reduced pressure. The residue was partitioned in between ethyl acetate and water. The layers were separated, the organic layer was washed with cold 2 N NaOH (10 mL), brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide 4-(2-amino-thiazol-5-yloxy)-3-fluoro-benzoic acid ethyl ester (0.68 gm).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][CH2:10][CH2:11][N:12]1[C:20]2[N:19]=[CH:18][NH:17][C:16]=2[C:15](=[O:21])[NH:14][C:13]1=[S:22].C(N(CC)CC)C.[N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([CH:40]=O)=[CH:32][CH:31]=1.C([BH3-])#N.[Na+]>>[CH3:8][N:9]([CH2:40][C:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:30]=[CH:31][CH:32]=1)[CH2:10][CH2:11][N:12]1[C:20]2[N:19]=[CH:18][NH:17][C:16]=2[C:15](=[O:21])[NH:14][C:13]1=[S:22]
Reactant: CNCCn1c(=S)[nH]c(=O)c2[nH]cnc21
Reactant: O=Cc1ccnc2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CN(CCn1c(=S)[nH]c(=O)c2[nH]cnc21)Cc1ccnc2ccccc12
Yield: 14.1 %

Procedure:
The title compound was prepared in accordance with the general method described in Example 26(c) by using 3-[2-(methylamino)ethyl]-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one trifluoroacetate (0.10 g, 0.29 mmol, obtained from Example 28(c)), triethylamine (0.032 mL, 0.32 mmol), 4-quinoline carboxaldehyde (0.060 g, 0.38 mmol) and sodium cyanoborohydride (0.028 g, 0.44 mmol) which yielded 0.015 g (14% yield) of the title compound.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:20].[C:21](Cl)(=[O:30])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl>[C:21]([NH:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:20])(=[O:30])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C=Cc1ccccc1)NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Reaction time: 16 h

Procedure:
3-(RS)-Amino-1,3-dihydro-5-(2'-fluorophenyl)-2H-1,4-benzodiazepin-2-one (50 mg, 0.186 mmol) was suspended in methylene chloride (1 ml). Cinnamoyl chloride (34.5 mg, 0.207 mol) was added to the methylene chloride mixture. The pH of the stirred mixture was adjusted to ~9 with 50 μl of triethylamine. After stirring for 16 hours the mixture was filtered. The product in the filtrate was purified by prep TLC. The product band was collected by washing the silica containing the product, with 80:20:2 CMW. The solvent was evaporated and the residue was dissolved in methanol, placed in a small vial and evaporated. Yield 16.6 mg.
Reaction SMILES: [CH:1]([C@H:14]1[CH2:20][C@H:19]2[C@H:17]([O:18]2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH2:30])=[CH:24][CH:23]=1>C(O)C>[CH:1]([C@H:14]1[CH2:20][C@H:19]([OH:18])[C@@H:17]([NH:30][CH2:29][CH2:28][C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)[CH2:16][O:15]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C(c2ccccc2)[C@H]2C[C@@H]3O[C@@H]3CO2)cc1
Reactant: NCCc1ccc(F)cc1
Solvent: CCO
Product: O[C@H]1C[C@H](C(c2ccccc2)c2ccccc2)OC[C@@H]1NCCc1ccc(F)cc1

Procedure:
(1R, 4R, 6S)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]-heptane 28c (0.02 g, 0.075 mmol) was reacted with 2-(4-fluorophenyl)-ethylamine (0.21 g, 1.50 mmol) in ethanol (Procedure E) to yield (2R, 4S, 5S)-2-benzhydryl-5-[2-(4-fluorophenyl)-ethylamino]-tetrahydropyran-4-ol, (+)-29c, 0.030g (98%, [α]D=(+)63.4, c=1, MeOH).
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[C:4]([CH3:24])[N:3]=1.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][C:26]1=[O:31]>C(O)CCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([N:28]3[CH2:29][CH2:30][NH:25][C:26](=[O:31])[CH2:27]3)=[N:3][C:4]=2[CH3:24])=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: O=C1CNCCN1
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Solvent: CCCCO
Product: Cc1nc(N2CCNC(=O)C2)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
Procedure F was performed using 100 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 84 mg of piperazine-2-one in 1 mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(3-oxopiperazin-1-yl)nicotinamide. MS (Q1) 422.3 (M)+.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:13]([O-:15])=[O:14])[NH:4][C:5](=[O:12])[CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.[OH-].[K+]>CO>[CH3:1][O:2][CH:3]([C:13]([OH:15])=[O:14])[NH:4][C:5](=[O:12])[CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(NC(=O)Cc1cccs1)C(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(NC(=O)Cc1cccs1)C(=O)O
Reaction time: 0.33 h

Procedure:
One gram of α-methoxy-N-(2-thienylacetyl)glycinate is dissolved in 10 ml methanol at 0°. Over 20 minutes, a solution of one equivalent of 10% KOH in methanol is added. After 15 minutes at 25° the solvent is evaporated and water is added. Addition of dilute HCl precipitates the title compound, which is extracted into ether and isolated by drying with MgSO4, filtering and evaporating ether.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:24])[CH2:22][CH3:23]>C(Cl)Cl>[C:21]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:24])[CH2:22][CH3:23]
Reactant: NCCCSc1ccncc1
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NCCCSc1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
To a solution of 700 mg (2.90 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 1.62 ml (11.6 mmol) of triethylamine in 30 ml of methylene chloride was added 0.30 ml (3.48 mmol) of propionyl chloride and the mixture was stirred at room temperature for 30 minutes. The reaction solution was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: methanol/ethyl acetate=1:10) to obtain the powder which was washed with ether and dried to obtain 483 mg of the desired compound (74.2%, yellow prisms), mp: 50.0°-51.0° C.
Reaction SMILES: C[C@H]1CCCCN1C1N2C=C(O[C@H]3C4C(=CC=CC=4)[C@@H](N)CC3)C=CC2=NN=1.[CH3:29][C@H:30]1[CH2:35][CH2:34][CH2:33][C@@H:32](C)[N:31]1[C:37]1[N:41]2[CH:42]=[C:43]([O:46][C@H:47]3[C:56]4[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=4)[C@@H:50]([NH:57][C:58](=[O:80])[NH:59][C:60]4[N:64]([C:65]5[CH:66]=[N:67][N:68]([CH2:70][CH2:71][O:72][S:73]([CH3:76])(=[O:75])=[O:74])[CH:69]=5)[N:63]=[C:62]([CH:77]([CH3:79])[CH3:78])[CH:61]=4)[CH2:49][CH2:48]3)[CH:44]=[CH:45][C:40]2=[N:39][N:38]=1>>[CH:77]([C:62]1[CH:61]=[C:60]([NH:59][C:58]([NH:57][C@@H:50]2[C:51]3[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=3)[C@H:47]([O:46][C:43]3[CH:44]=[CH:45][C:40]4[N:41]([C:37]([N:31]5[CH2:32][CH2:33][CH2:34][CH2:35][C@@H:30]5[CH3:29])=[N:38][N:39]=4)[CH:42]=3)[CH2:48][CH2:49]2)=[O:80])[N:64]([C:65]2[CH:66]=[N:67][N:68]([CH2:70][CH2:71][O:72][S:73]([CH3:76])(=[O:75])=[O:74])[CH:69]=2)[N:63]=1)([CH3:78])[CH3:79]
Reactant: CC(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5[C@H](C)CCC[C@@H]5C)n4c3)c3ccccc32)n(-c2cnn(CCOS(C)(=O)=O)c2)n1
Agent: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Product: CC(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)n(-c2cnn(CCOS(C)(=O)=O)c2)n1

Procedure:
The title compound was prepared starting from Intermediate 2 (150 mg, 0.397 mmol), and Intermediate Ac (163 mg, 0.397 mmol) by using an analogous procedure to that described for Intermediate A step d. LCMS (Method 3): Rt 3.21 min, m/z=639 [MH+].
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])=[O:8]>CS(C)=O.O>[N:1]([CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])=[O:8])=[N+:2]=[N-:3]
Reactant: COc1ccccc1C(=O)CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccccc1C(=O)CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.7 %

Procedure:
Add sodium azide (2.14 g, 32.92 mmol) to a solution of 2-bromo-2′-methoxyacetophenone (5.01 g, 21.87 mmol) in 75 ml of DMSO. Stir the mixture at ambient temperature for 18 hours and dilute it with 250 ml of water. Extract the mixture with ether (3×). Dry the combined organic layers with MgSO4. Filter off the drying agent and concentrate in vacuo to afford 3.54 g of 2-azido-1-(2-methoxyphenyl)-ethanone.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#N)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl.[OH-:21].[Na+]>C1(C)C=CC=CC=1.O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:21])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: N#Cc1ccc(N)nc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1ccc(C=O)cn1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1 g of 6-aminopyridine-3-carbonitrile in 20 mL of toluene cooled to −78° C. are added dropwise 15 mL of a 1.2 M solution of diisobutylaluminum hydride in toluene. The reaction medium is stirred for 30 minutes at −78° C. and is then allowed to warm slowly to 20° C. After cooling again to −78° C., 6 mL of water are added slowly and the resulting mixture is stirred for 1 hour at −78° C. The reaction medium is stirred for 16 hours at 20° C., treated with 20 mL of 2.5 N hydrochloric acid, stirred for 20 minutes, basified by addition of concentrated sodium hydroxide and extracted three times with 100 mL of dichloromethane. The combined organic phases are dried and concentrated to dryness under reduced pressure. The residue is taken up in 40 mL of ethyl acetate and 40 mL of saturated sodium bisulfite solution. The aqueous phase is washed twice with 40 mL of ethyl acetate, basified to about pH 14 by addition of concentrated sodium hydroxide, and extracted three times with 50 mL of dichloromethane. The combined organic phases are dried and concentrated to dryness under reduced pressure to give 200 mg of crude 6-aminopyridine-3-carboxaldehyde in the form of a yellow powder, which is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH3:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21](O)=[O:22]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:21]([C:17]2[S:18][CH:19]=[CH:20][C:16]=2[CH3:15])=[O:22])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: Cc1ccsc1C(=O)O
Product: Cc1ccsc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (50 mg) and 3-methyl-2-thiophenecarboxylic acid to produce N-(4-chloro-3-(pyridin-2-yl)phenyl)-3-methylthiophene-2-carboxamide. MS (Q1) 329.0 (M)+.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[N:4]1.Br[CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[O:13]([CH2:12][CH2:11][N:3]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[N:4]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1cn[nH]c1
Reactant: BrCCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cnn(CCOc2ccccc2)c1
Temperature: 25 °C
Yield: 73.9 %

Procedure:
Sodium hydride (60%, 6.3 g, 1.0 eq) was added to a solution of 1H-pyrazole-4-carbaldehyde (15 g, 156 mmol) in DMF (150 ml) at 0° C. The mixture was allowed to warm and was stirred at room temperature. (2-Bromoethoxy)benzene (30.2 g, 1 eq) was then added and the resulting mixture was stirred overnight at room temperature. It was quenched by addition of aqueous ammonium chloride, diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography using a hexane/EtOAc gradient (10:1 to 0:100). Pure fractions were combined and evaporated under reduced pressure to yield 1-(2-phenoxyethyl)-1H-pyrazole-4-carbaldehyde (24 g, 71%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][CH2:12][NH:13][C:14]([NH:16][C@@H:17]([C:28]([NH:30][C@H:31]([C:47]([N:49]1[CH2:54][CH2:53][N:52]([C:55]2[CH:60]=[CH:59][N:58]=[CH:57][CH:56]=2)[CH2:51][CH2:50]1)=[O:48])[CH2:32][CH2:33][CH2:34][CH2:35][NH:36]C(OCC1C=CC=CC=1)=O)=[O:29])[CH2:18][C:19]1[CH:24]=[C:23]([Br:25])[C:22]([OH:26])=[C:21]([Br:27])[CH:20]=1)=[O:15].Br.C(OCC)C>C(O)(=O)C.C1(OC)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][CH2:12][NH:13][C:14]([NH:16][CH:17]([C:28]([NH:30][C@H:31]([C:47]([N:49]1[CH2:50][CH2:51][N:52]([C:55]2[CH:60]=[CH:59][N:58]=[CH:57][CH:56]=2)[CH2:53][CH2:54]1)=[O:48])[CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])=[O:29])[CH2:18][C:19]1[CH:24]=[C:23]([Br:25])[C:22]([OH:26])=[C:21]([Br:27])[CH:20]=1)=[O:15]
Reactant: COc1ccc(OC)c(CCNC(=O)N[C@H](Cc2cc(Br)c(O)c(Br)c2)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2)C(=O)N2CCN(c3ccncc3)CC2)c1
Agent: Br
Solvent: COc1ccccc1
Solvent: CC(=O)O
Solvent: CCOCC
Product: COc1ccc(OC)c(CCNC(=O)NC(Cc2cc(Br)c(O)c(Br)c2)C(=O)N[C@@H](CCCCN)C(=O)N2CCN(c3ccncc3)CC2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 0.8 g (0.84 mmol) of 1-[N2—[N-[[[2-(2,5-dimethoxyphenyl)ethyl]amino]carbonyl]-3,5-dibromo-D-tyrosyl]-N6-[(phenylmethoxy)carbonyl]-L-lysyl]-4-(4-pyridinyl)-piperazine, 50 ml of glacial acetic acid, 25 ml of a 33% solution of hydrogen bromide in glacial acetic acid and 2 ml of anisole was stirred for 12 hours at ambient temperature. The reaction mixture was stirred into diethylether and the resulting precipitate was suction filtered. The solid residue was purified by column chromatography (MN-silica gel 60, Macherey-Nagel, 70-230 mesh ASTM, eluant:ethyl acetate/methanol/conc. aqueous ammonia=8/2/0.2 (v/v/v)). 0.3 g (44% of theory) of the desired product was obtained as an amorphous solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][NH:15][C:16]([C:18]2[C:19]3[CH2:20][C@H:21]4[CH2:34][C@H:22]4[C:23]=3[N:24]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[F:33])[N:25]=2)=[O:17])[CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[NH:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][NH:15][C:16]([C:18]2[C:19]3[CH2:20][C@H:21]4[CH2:34][C@H:22]4[C:23]=3[N:24]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[F:33])[N:25]=2)=[O:17])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCOC(CNC(=O)c2nn(-c3ccc(F)cc3F)c3c2C[C@H]2C[C@@H]32)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NCC1CNCCO1)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Temperature: 23 °C
Reaction time: 2.5 h
Yield: 81.5 %

Procedure:
To 2-({[(1aR,5aR)-2-(2,4-Difluoro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-methyl)-morpholine-4-carboxylic acid tert-butyl ester (140 mg, 0.295 mmol) was added a 4.0 M dioxane solution of HCl (2.213 mL, 8.85 mmol). The solution was stirred at 23° C. for 2.5 h then concentrated. The residue was taken up in diethyl ether (8 mL). The resulting precipitate was collected by filtration then dried under reduced pressure to provide the title compound (hydrochloride salt, 90 mg). LCMS m/z=375.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.40 (td, J=4.5, 3.4 Hz, 1H), 1.14-1.19 (m, 1H), 2.16-2.20 (m, 1H), 2.25-2.31 (m, 1H), 2.70-2.78 (m, 2H), 2.87-3.00 (m, 2H), 3.13-3.21 (m, 2H), 3.23-3.32 (m, 2H), 3.66-3.73 (m, 1H), 3.80-3.86 (m, 1H), 3.95 (dd, J=12.6, 3.1 Hz, 1H), 7.29-7.34 (m, 1H), 7.58-7.64 (m, 1H), 7.78 (td, J=8.9, 5.9 Hz, 1H), 8.17 (t, J=6.1 Hz, 1H), 9.14 (bs, 2H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[F:11][C:12]1[CH:13]=[CH:14][C:15]2[N:21]([CH3:22])[C:20](=[O:23])[CH2:19][N:18]=[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:16]=2[CH:30]=1.CC(C1C=C(C(C)C)C(S([N:46]=[N+:47]=[N-:48])(=O)=O)=C(C(C)C)C=1)C.C(O)(=O)C>>[N:46]([CH:19]1[N:18]=[C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16]2[CH:30]=[C:12]([F:11])[CH:13]=[CH:14][C:15]=2[N:21]([CH3:22])[C:20]1=[O:23])=[N+:47]=[N-:48]
Reactant: CN1C(=O)CN=C(c2ccccc2)c2cc(F)ccc21
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CC(=O)O
Product: CN1C(=O)C(N=[N+]=[N-])N=C(c2ccccc2)c2cc(F)ccc21
Yield: 82.7 %

Procedure:
As illustrated in the scheme above and following General Procedure 6, KHMDS (1.34 mL of 0.5 M in toluene, 0.670 mmol), 7-fluoro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (0.171 g, 0.637 mmol), trisyl azide (0.493 g, 1.59 mmol) and acetic acid (0.16 mL, 2.8 mmol) were combined. After workup, purification of the crude product by silica gel column chromatography (100% CH2Cl2 to 9:1 CH2Cl2:EtOAc) provided the title compound as a pale yellow solid (0.163 g, 83%). 1H-NMR (CDCl3): δ 7.72-7.67 (m, 2H), 7.54-7.49 (m, 1H), 7.47-7.42 (m, 2H), 7.39 (dd, J=4.8 Hz, J=9.2 Hz, 1H), 7.36-7.30 (m, 1H), 7.08 (dd, J=2.8 Hz, J=8.4 Hz, 1H), 4.55 (s, 1H), 3.45 (s, 3H). MS (ESI) (M+H)+=310.