Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[N:25][O:26][CH3:27])[CH:10]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[CH3:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1>C(#N)C>[Cl:1][C:2]1[C:3](/[C:9](=[N:25]\[O:26][CH3:27])/[CH:10]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:22])([F:21])[F:23])[CH3:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CON=C(c1ncc(Cl)cc1Cl)C(C)NC(=O)c1ccccc1C(F)(F)F
Solvent: CC#N
Product: CO/N=C(\c1ncc(Cl)cc1Cl)C(C)NC(=O)c1ccccc1C(F)(F)F
Yield: 20.6 %

Procedure:
160 mg of N-[2-(3,5-dichloropyridin-2-yl)-2-methoxyimino-1-methylethyl]-2-(trifluoromethyl)benzamide in 4 ml of acetonitrile was irradiated with light for 12 hours in a quartz cell (manufactured by Fine, 4 clear windows for spectroscopy) using a 100 W high-pressure mercury lamp (manufactured by USHIO INC., lamp: UM-102, power supply: UM-103B-B). After completion of the reaction, the solvent was evaporated under reduced pressure, and the precipitated solid was washed with 5 ml of diisopropyl ether to obtain 33 mg of the desired product as white crystals.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=3)[N:12]([CH:22]([CH3:24])[CH3:23])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:16]=[C:17]([C:32]4[CH:31]=[C:30]([F:33])[CH:29]=[CH:28][C:27]=4[Cl:26])[CH:18]=[CH:19][CH:20]=3)[N:12]([CH:22]([CH3:24])[CH3:23])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)N1C(=O)N(S(=O)(=O)c2ccccc2)CC1c1cccc(Br)c1
Reactant: OB(O)c1cc(F)ccc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)N1C(=O)N(S(=O)(=O)c2ccccc2)CC1c1cccc(-c2cc(F)ccc2Cl)c1

Procedure:
In analogy to example 1, step 3,1-benzenesulfonyl-4-(3-bromo-phenyl)-3-isopropyl-imidazolidin-2-one (example 12, step 1) was reacted with 2-chloro-5-fluorophenylboronic acid in the presence of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct and sodium carbonate in dioxane/water to give 1-benzenesulfonyl-4-(2′-chloro-5′-fluoro-biphenyl-3-yl)-3-isopropyl-imidazolidin-2-one as a light yellow oil. MS: 472.9 ([M+H]+)
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH:13]=O)[CH:4]=[N:3]1.[H-].[Na+].C(OP([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])(OCC)=O)C.CN(C)C=O>O>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:5](/[CH:13]=[CH:25]/[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:4]=[N:3]1
Reactant: Cn1ncc(C=O)c1-c1cccnc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1cnn(C)c1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
A mixture of 1-methyl-5-(3-pyridinyl)-1H-pyrazole-4-carbaldehyde (750 mg), sodium hydride (60% in oil, 176 mg), ethyl diethylphosphonoacetate (1.08 g) and N,N-dimethylformamide (8 ml) was stirred at room temperature for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. Recrystallization of the residue from ethyl acetate-hexane gave ethyl (2E)-3-[1-methyl-5-(3-pyridinyl)-1H-pyrazol-4-yl]acrylate (770 mg, 75%) as pale-yellow prism crystals. melting point: 159-160° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[C:15]([N+:19]([O-:21])=[O:20])[C:16]=1[O:17][CH3:18])[C:6]([CH2:8][C:9](OCC)=[O:10])=O.[CH3:22][NH:23][NH2:24]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[CH:8]=[C:9]([OH:10])[N:23]([CH3:22])[N:24]=2)[CH:14]=[C:15]([N+:19]([O-:21])=[O:20])[C:16]=1[O:17][CH3:18]
Reactant: CCOC(=O)CC(=O)c1cc(OC)c(OC)c([N+](=O)[O-])c1
Reactant: CNN
Solvent: CCO
Product: COc1cc(-c2cc(O)n(C)n2)cc([N+](=O)[O-])c1OC

Procedure:
10 g of ethyl (3,4-dimethoxy-5-nitrobenzoyl)acetate are suspended in 100 ml of ethanol, treated with 1.7 g of methylhydrazine and heated under reflux for 16 hours. After distillation of about 50 ml of ethanol, the mixture is cooled to 0° and the separated precipitate is filtered under suction. After recrystallization from ethanol there is obtained 3-(3,4-dimethoxy-5-nitrophenyl)-1-methylpyrazol-5-ol in the form of yellow crystals of m.p. 200°-202°.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27]([CH:29]3[CH2:34][CH2:33][N:32]([C:35]4[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=4)[CH2:31][CH2:30]3)=[O:28])[CH:24]=2)[N:19](C2CCCCO2)[N:18]=1>C(Cl)Cl>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:27]([CH:29]3[CH2:30][CH2:31][N:32]([C:35]4[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=4)[CH2:33][CH2:34]3)=[O:28])[CH:24]=2)[NH:19][N:18]=1
Reactant: O=C(Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1)C1CCN(c2ccncc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc2[nH]nc(-c3nc4ccccc4[nH]3)c2c1)C1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.6 %

Procedure:
TFA (0.5 mL, 6.90 mmol) was added to a solution of N-(3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-1-(pyridin-4-yl)piperidine-4-carboxamide (12 mg, 0.023 mmol) in CH2Cl2 (4 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound (7 mg) as an off-white solid. 1H NMR (400 MHz, CD3OD): δ 8.50 (s, 1H), 8.10 (m, 2H), 7.73 (d, 1H, J=8.8 Hz), 7.65 (m, 2H), 7.57 (d, 1H, J=9.2 Hz), 7.27 (m, 2H), 6.94 (m, 2H), 4.17 (m, 2H), 3.11 (m, 2H), 2.77 (m, 1H), 2.03 (m, 2H), 1.89 (m, 2H); ESI-MS [M+2H/2]+: 219.61.
Reaction SMILES: Cl[CH:2](P(=O)(OCC)OCC)[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[CH:18]([C:20]1[CH:29]=[CH:28][C:27]2[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=2[CH:21]=1)=O>>[CH3:30][C:26]1([CH3:31])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]2[CH:21]=[C:20]([C:18]#[C:2][C:3]3[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=3)[CH:29]=[CH:28][C:27]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C=O)ccc21
Reactant: CCOP(=O)(OCC)C(Cl)c1ccc(C)cc1
Product: Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Yield: 55.8 %

Procedure:
Using a process similar to that described in Example 13, 61.4 g (0.22 mole) of diethyl 1-chloro-1-(4-tolyl)-methylphosphonate, 51.1 g (0.22 mole) of 2-formyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnapthalene and 50 g (0.44 mole) of potassium tert.-butylate were reacted for 1 hour to give 37.1 g (56%) of the title compound of melting point 99° C., the reaction mixture being poured onto water and acidified, and the precipitated solid being filtered off under suction and recrystallized twice from methanol.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10]([O:14][C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([OH:21])=O)=[O:16])([CH3:13])([CH3:12])[CH3:11].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH2:47]([N:54]1[CH:62]=[C:61]2[C:56]([CH:57]=[C:58]([C:63]3[CH:64]=[C:65]([CH:73]4[CH2:78][CH2:77][NH:76][CH2:75][CH2:74]4)[N:66]4[C:71]=3[C:70]([NH2:72])=[N:69][CH:68]=[N:67]4)[CH:59]=[CH:60]2)=[N:55]1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CN(C=O)C>[C:10]([O:14][C:15]([N:17]1[CH2:24][CH2:23][CH2:22][CH:18]1[C:19]([N:76]1[CH2:77][CH2:78][CH:73]([C:65]2[N:66]3[C:71]([C:70]([NH2:72])=[N:69][CH:68]=[N:67]3)=[C:63]([C:58]3[CH:59]=[CH:60][C:61]4[C:56]([CH:57]=3)=[N:55][N:54]([CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:62]=4)[CH:64]=2)[CH2:74][CH2:75]1)=[O:21])=[O:16])([CH3:11])([CH3:12])[CH3:13]
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
N,N-Diisopropylethylamine (35.0 μL, 0.200 mmol, 2.0 eq.) was added to N-(tert-butoxycarbonyl)-L-proline (23.7 mg, 0.110 mmol, 1.1 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (19.2 mg, 0.100 mmol, 1.0 eq), 1-hydroxybenzotriazole (13.5 mg, 0.100 mmol, 1.0 eq) and 1 mL of anhydrous DMF. The reaction was cooled to 0° C. and shaken for 30 minutes. Then to this mixture was added 5-(2-benzyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (42.3 mg, 0.1 mmol, 1.0 eq.) in 1 mL of anhydrous DMF. The reaction was shaken for 5 minutes at 0° C. The reaction was slowly warmed to rt and shaken over night. The product was purified by acidic HPLC on a Sunfire column (5% to 90%, 12 min).
Reaction SMILES: [C:1]([C:9]1[C:16]([Cl:17])=[CH:15][C:12]([CH2:13]Br)=[CH:11][C:10]=1[Cl:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:19]=[N+:20]=[N-:21].[Na+]>C(O)C>[C:1]([C:9]1[C:16]([Cl:17])=[CH:15][C:12]([CH2:13][N:19]=[N+:20]=[N-:21])=[CH:11][C:10]=1[Cl:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1c(Cl)cc(CBr)cc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Product: [N-]=[N+]=NCc1cc(Cl)c(C(=O)c2ccccc2)c(Cl)c1
Yield: 212.3 %

Procedure:
A mixture of 4-benzoyl-3,5-dichlorobenzyl bromide (2.37 g, 6.89 mmol) and sodium azide (1.32 g, 20:3 mmol) in absolute ethanol (31 ml) was refluxed 5 hours, cooled, and evaporated. The residue was dissolved in diethyl ether and filtered. The filtrate was evaporated to provide 1.95 g (92%) 4-benzoyl-3,5-dichorobenzyl azide, IR (neat): 2090, 1670 cm-1.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][C:10](OCC)=[O:11])[S:2]1.[Cl-].[Na+].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[S:2]1
Reactant: CCOC(=O)CCCCC1CCSS1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: OCCCCCC1CCSS1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of ethyl 5-(1,2-dithiolan-3-yl)pentanoate in 40 ml of anhydrous tetrahydrofuran was added dropwise, whilst cooling with ice and sodium chloride, to a suspension of 3.34 g of lithium aluminum hydride in 150 ml of anhydrous tetrahydrofuran. The resulting mixture was stirred at room temperature for 3 hours and 30 minutes. Sodium sulfate decahydrate was then added, whilst cooling with ice and sodium chloride, to the reaction mixture, and then the mixture was stirred at room temperature for 3 hours. The reaction mixture was allowed to stand overnight at room temperature, and then insoluble matter was filtered off using a Celite (trade mark) filter aid. The solvent was removed from the filtrate by distillation under reduced pressure. 50 ml of methanol, 25 ml of a 1 N aqueous solution of sodium hydroxide and 10 ml of 2 N aqueous hydrochloric acid were then added to the residue. Air was then blown into the resulting mixture. Five drops of a 1% aqueous solution of ferric chloride were added dropwise to the reaction mixture, and then the mixture was stirred at room temperature for one hour. The reaction mixture was allowed to stand overnight at room temperature, and then the solvent was removed by distillation under reduced pressure. Water was added to the residue, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. Ethyl acetate was removed from the extract by distillation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 1:2 and 1:1 by volume mixtures of ethyl acetate and hexane as eluent. The solvent was removed from the resulting eluate by distillation under reduced pressure, and 30 ml of toluene were added to the residue. 1 ml was taken from the resulting solution, and the solvent was removed by distillation under reduced pressure, to give 0.13 g of the title compound as a yellow oil having an Rf value of 0.39 (silica gel thin layer chromatography; using a 1:1 by volume mixture of ethyl acetate and hexane as the eluent).
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([CH2:11][CH3:12])[CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1OB(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[C:2]1[N:7]2[N:8]=[C:9]([CH2:11][CH3:12])[CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)Oc1ccc(Cl)cc1Cl
Reactant: CCc1cc2cccc(Br)n2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CCc1cc2cccc(-c3ccc(Cl)cc3Cl)n2n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
After dissolving 7-bromo-2-ethylpyrazolo[1,5-a]pyridine (300 mg) in ethanol (2 mL) and toluene (4 mL), 2,4-dichlorophenylboric acid (508 mg), tetrakis(triphenylphosphine)palladium(0) complex (154 mg) and 2M aqueous sodium carbonate (1.33 mL) were added and the mixture was heated and stirred at 80° C. for 3 hours under a nitrogen stream. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the organic layer washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (380 mg) was obtained from the n-hexane:ethyl acetate (100:1) fraction as a light yellow oil.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].O[C@@H]1[C@H:15]2[C@H:16]3[C@H:25]([CH2:26][CH2:27][C@:12]2([CH2:13][CH3:14])[C:11](=[O:29])C1)[C@@H:24]1[C:19](=[CH:20][C:21](=[O:28])[CH2:22][CH2:23]1)[CH2:18][CH2:17]3>N1C=CC=CC=1>[C:5]([O:4][C@@H:1]1[C@H:15]2[C@H:16]3[C@H:25]([CH2:26][CH2:27][C@:12]2([CH2:13][CH3:14])[C:11](=[O:29])[CH2:2]1)[C@@H:24]1[C:19](=[CH:20][C:21](=[O:28])[CH2:22][CH2:23]1)[CH2:18][CH2:17]3)(=[O:7])[CH3:6]
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](O)CC2=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(C)=O)CC2=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
200 ml of acetic anhydride is added dropwise to 100 g of 15α-hydroxy-18-methyl-4-estrene-3,17-dione in 350 ml of pyridine. After one hour, the reaction mixture is stirred into ice water. The thus-precipitated product is suctioned off, washed neutral with water, and dried under vacuum at 50° C., thus obtaining 100 g of 15α-acetoxy-18-methyl-4-estrene-3,17-dione. A sample recrystallized from acetone/hexane melts at 165° C.
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(F)=CC=1)C.C=O.[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[CH2:30][CH2:31][NH2:32].[F:33][C:34]1[CH:52]=[CH:51][C:37]([CH2:38][N:39]([CH3:50])[C:40]([C:42]2[CH2:43]N(C)[C:45](=[O:48])[C:46]=2[OH:47])=[O:41])=[CH:36][CH:35]=1>>[F:33][C:34]1[CH:52]=[CH:51][C:37]([CH2:38][N:39]([CH3:50])[C:40]([C:42]2[CH2:43][N:32]([CH2:31][CH2:30][C:24]3[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:23]=3[Cl:22])[C:45](=[O:48])[C:46]=2[OH:47])=[O:41])=[CH:36][CH:35]=1
Reactant: NCCc1ccc(Cl)cc1Cl
Reactant: CN1CC(C(=O)N(C)Cc2ccc(F)cc2)=C(O)C1=O
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(F)cc1
Product: CN(Cc1ccc(F)cc1)C(=O)C1=C(O)C(=O)N(CCc2ccc(Cl)cc2Cl)C1

Procedure:
3-[(4-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 1-D) was treated with paraformaldehyde and 2-(2,4-dichloro-phenyl)-ethylamine as described in the preparation of Compound 1. 1H NMR (500 MHz, CDCl3) δ: 2.99 (s, 3), 3.03 (t, 2, J=7), 3.74 (t, J=7), 4.06 (s, 2), 4.60 (s, 2), 7.03–7.37 (overlapping m, 7). 13C NMR (125 MHz, CDCl3) δ: 31.76, 34.67, 42.95, 49.48, 51.61, 109.74, 115.76, 115.93, 127.53, 129.27, 129.32, 129.53, 131.63, 131.78, 131.80, 133.57, 134.14, 134.65, 152.19, 161.44, 163.40, 165.24, 165.98.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:25])([C:21]([F:24])([F:23])[F:22])[CH2:7][CH2:8][N:9]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[C:11]([C:18](=[NH:20])[NH2:19])=[N:10]1.C([N:28](CC)CC)C.O.NN>C(O)C>[F:25][C:6]([F:5])([C:21]([F:22])([F:23])[F:24])[CH2:7][CH2:8][N:9]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[C:11]([C:18](=[NH:19])[NH:20][NH2:28])=[N:10]1
Reactant: CCN(CC)CC
Reactant: N=C(N)c1nn(CCC(F)(F)C(F)(F)F)c2ncccc12
Agent: NN
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: N=C(NN)c1nn(CCC(F)(F)C(F)(F)F)c2ncccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.6 g (about 1.144 mmol) of the compound from Example 13A were dissolved in ml of ethanol, and 462 mg (4.574 mmol) of triethylamine and 71 mg (1.144 mmol) of hydrazine hydrate (80% strength solution in water) were added at 0° C. The mixture was stirred at RT overnight and then concentrated on a rotary evaporator. This gave 689 mg (purity about 60%) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2.[CH3:27][O:28][C:29]1[N:34]=[C:33]([C:35](O)=[O:36])[CH:32]=[CH:31][CH:30]=1>>[CH3:26][CH:6]1[CH2:5][C@H:4]2[C@H:8]([CH2:9][N:10]([C:11]([C:13]3[N:14]=[C:15]([CH3:25])[S:16][C:17]=3[C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[O:12])[C@@H:3]2[CH2:2][NH:1][C:35]([C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([O:28][CH3:27])[N:34]=2)=[O:36])[CH2:7]1
Reactant: COc1cccc(C(=O)O)n1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CN)c1
Product: COc1cccc(C(=O)NC[C@@H]2[C@H]3CC(C)C[C@H]3CN2C(=O)c2nc(C)sc2-c2cccc(C)c2)n1

Procedure:
prepared by reaction of [(1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]oct-3-yl]-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 6-methoxy-pyridine-2-carboxylic acid.
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.C([Mg]Br)(C)C.[C:20]([C:28]([O:30][CH2:31][CH3:32])=[O:29])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[C:9]([O:8][C:6]([C:5]1[CH:13]=[CH:14][C:2]([C:20]([OH:27])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:3][CH:4]=1)=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: CCOC(=O)C(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(I)cc1
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: CCOC(=O)C(O)(c1ccccc1)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: -40 °C
Reaction time: 1 h
Yield: 21.9 %

Procedure:
To a stirred solution of tert-butyl 4-iodobenzoate (0.304 g, 1.0 mmol) in 10 mL THF at −40° C. was added a solution of isopropylmagnesium bromide (1.05 ml, 1.05 mmol, 1M in THF) dropwise under argon. After stirring for 1 hour at −40° C., ethyl benzoylformate (0.175 ml, 1.1 mmol) was added dropwise and the cold bath allowed to warm to room temperature over a 40 min. period. The reaction was quenched by the addition of an aqueous solution of 20% ammonium chloride. The reaction mixture was extracted twice with ether, the combined organic layers washed with brine, dried over Na2SO4 and was evaporated to give an oil that was chromatographed on 10 g silica gel using a gradient elution from 0-40% EtOAc in Hexanes. Product containing fractions were combined and concentrated to give (0.078 g, 22%) ethyl (4-tert-butyloxycarbonylphenyl)(hydroxy)phenylacetate as a colorless oil. NMR, 400 MHz (CDCl3) 7.95 ppm (d, J=8.55 Hz, 2H), 7.52 ppm (d, J=8.55 Hz, 2H), 7.30-7.40 ppm (m, 5H), 4.33 ppm (q, J=7.08 Hz, 2H), 4.29 ppm (s, OH, 1H), 1.59 ppm (s, 9H), 1.28 ppm (t, J=7.08 Hz, 3H).
Reaction SMILES: [OH:1][NH:2][C:3](=[O:22])[C:4]([CH2:19][CH:20]=[CH2:21])([S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH2:5][CH:6]=[CH2:7]>CO.[Pd]>[OH:1][NH:2][C:3](=[O:22])[C:4]([S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)(=[O:9])=[O:10])([CH2:19][CH2:20][CH3:21])[CH2:5][CH2:6][CH3:7]
Reactant: C=CCC(CC=C)(C(=O)NO)S(=O)(=O)c1ccc(OC)cc1
Agent: [Pd]
Solvent: CO
Product: CCCC(CCC)(C(=O)NO)S(=O)(=O)c1ccc(OC)cc1

Procedure:
2-allyl-2-(4-methoxy-benzenesulfonyl)-pent4enoic acid hydroxyamide (326 mg, 1.0 mmol) (example 26) was dissolved in methanol (50 ml) and hydrogenated over 10% Pd/C (100 mg) at room temperature, under 49 psi pressure for 4 hours. At the end, the reaction mixture was filtered and methanol was removed. The resulting solid was crystallized from methanol. Yield: 250 mg, 75%; MS: 330 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 0.92 (t, J=4.0 Hz, 6H), 1.27-1.59 (m, 4H), 1.78-2.02 (m, 4H), 3.86 (s, 3H), 6.04 (bs, 1H), 6.97 (d, J=9Hz, 2H), 7.76 (d,J=9 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9](I)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[N:32]1[C:41]2[C:36](=[CH:37][C:38](B(O)O)=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1.C(=O)(O)[O-]>CN(C)C=O.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>[F:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([C:38]3[CH:37]=[C:36]4[C:41](=[CH:40][CH:39]=3)[N:32]=[CH:33][CH:34]=[CH:35]4)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc32)cc1
Reactant: OB(O)c1ccc2ncccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2c(-c3ccc4ncccc4c3)cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc32)cc1
Temperature: 70 °C

Procedure:
To a stirred ambient solution of 1-(5-(5-fluoro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanol (Example 59A) (200 mg, 0.351 mmol) and quinoline-6-boronic acid (91 mg, 0.527 mmol) in N,N-dimethylformamide (2.63 mL) was added saturated aqueous bicarbonate solution (880 μL) followed by bis(triphenylphosphine)palladium dichloride (17.26 mg, 0.025 mmol). The mixture was heated to 70° C. for 16 hours and was quenched by the addition of water and dichloromethane. The layers were separated, and the aqueous layer was extracted with additional dichloromethane. The combined organics were dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give crude product. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 100% ethyl acetate in hexane, to give the title compound. MS ESI(+) m/z 571.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:17]2[N:21]([CH3:22])[N:20]=[C:19]([CH:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)[N:18]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:11][N:12]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:13]([C:10]1[O:9][C:8]([C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([C:17]3[N:21]([CH3:22])[N:20]=[C:19]([CH:23]4[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]4)[N:18]=3)[N:6]=2)=[N:12][N:11]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: Cn1nc(C2CCN(C(=O)OC(C)(C)C)CC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nc(C2CCNCC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Yield: 85.8 %

Procedure:
A solution of tert-butyl 4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-methyl-1H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (3 g, 6.20 mmol) in TFA (15 mL) and CH2Cl2 (15 mL) was stirred at 25° C. for 1 hour. The mixture was azeotroped with toluene, a 7N solution of ammonia in methanol and dichloromethane were added and the mixture was adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel eluting with 0 to 8% methanol in dichloromethane followed by 0 to 10% methanolic ammonia in dichloromethane. The solvent was evaporated to dryness to afford 3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-(1-methyl-3-(piperidin-4-yl)-1H-1,2,4-triazol-5-yl)pyrazin-2-amine (2.040 g, 86%) as a yellow crystalline solid: 1H NMR Spectrum: (DMSO-d6) 1.45 (9H, s), 1.55-1.66 (2H, m), 1.86 (2H, dd), 2.52-2.61 (2H, m), 2.69-2.78 (1H, m), 2.95-3.02 (2H, m), 4.20 (3H, s), 8.86 (1H, s); Mass Spectrum [M+H]+=384.