Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:15]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:44]([N:51]1[CH2:56][CH2:55][N:54]([CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[CH2:53][CH:52]1[CH2:64][OH:65])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C1COCC1>[CH2:44]([N:51]1[CH2:56][CH2:55][N:54]([CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[CH2:53][CH:52]1[CH2:64][O:65][C:18]1[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][CH:15]=[C:14]([F:13])[C:19]=1[F:20])[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: O=[N+]([O-])c1cc(O)c(F)c(F)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)c(F)c1OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 6043.8 %

Procedure:
(1Ba) A solution of 4.7 g (27 mmol) of diethyl azodicarboxylate in 15 ml of THF was added dropwise at 15° C. while stirring to a solution of 3.9 g (22.5 mmol) of 2,3-difluoro-5-nitrophenol, 7.1 g (27 mmol) of triphenylphosphine and 8 g (0.27 mmol) of 1,4-dibenzyl-2-hydroxymethylpiperazine in 250 ml of THF. The yellow reaction solution was then stirred at room temperature for an additional 3 hours. After concentrating the reaction solution, the oily residue was stirred with a total of 2 l of hot n-hexane in several portions. The hexane solution was separated and cooled. The separated triphenylphosphine oxide was removed by filtration under suction, and the filtrate was concentrated. Chromatography on silica gel with ether/n-hexane (1:1) as the eluent gave 7.4 g of 1,4-dibenzyl-2-[(6-nitro-2,3-difluorophenoxy)methyl]piperazine as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)=[N:12][N:11]=1.C(O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>CC(O)CC.C(Cl)Cl>[CH3:26][N:23]1[CH2:22][CH2:21][N:20]([C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=3)=[N:11][N:12]=2)[CH2:25][CH2:24]1
Reactant: CN1CCN(c2nnc(Cl)c3ccccc23)CC1
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCC(C)O
Product: CN1CCN(c2nnc(Nc3ccc(O)cc3)c3ccccc23)CC1

Procedure:
A mixture of 4-aminophenol (42 mg, 0.38 mmol), 1-chloro-4-(4-methylpiperazin-1-yl)phthalazine (100 mg, 0.381 mmol), and TFA (29 μA 0.38 mmol) was heated in 2-butanol (3 mL) in a sealed tube at 90° C. overnight. Next day LC/MS shows completion of reaction. The reaction was cooled and diluted with DCM. Aqueous sodium bicarbonate was added and the organic layer was collected. The aqueous layer was neutralized with 1N HCl and the product was extracted with DCM. The organic layers were combined, dried over sodium sulfate, and concentrated to afford 4-(4-(4-methylpiperazin-1-yl)phthalazin-1-ylamino)phenol as solid brown material. MS [M+H]=336.2. Calc'd for C19H21N5O: 335.4.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C1([Mg]Cl)C=CC=CC=1.[CH:21](=[O:25])[CH:22]([CH3:24])[CH3:23]>C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:21]([OH:25])[CH:22]([CH3:24])[CH3:23])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: CC(C)C=O
Reactant: COc1ccc(I)c([N+](=O)[O-])c1
Agent: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(C(O)C(C)C)c([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 0.08 h
Yield: 66.6 %

Procedure:
To a solution of 4-iodo-3-nitroanisole (2.79 g, 10.0 mmol) in anhydrous THF (20 mL) at minus 40° C. under a nitrogen atmosphere, phenylmagnesium chloride (2 M in THF, 6.0 mL, 12 mmol) was added dropwise at a rate such that the temperature would not exceed minus 35° C. Upon completion of the addition, the mixture was stirred at minus 40° C. for five min, followed by addition of isobutyraldehyde (1.8 mL, 20 mmol). The mixture was gradually warmed to room temperature, quenched with saturated NH4Cl solution (5.0 mL), diluted with CH2Cl2 (100 mL) and washed with water (100 mL). The organic phase was separated, and the aqueous phase was extracted with CH2Cl2 (50 mL) three times. The combined organic phase was washed with brine (40 mL), dried over Na2SO4, concentrated in vacuo, and the residue was purified by silica gel column chromatography to yield (R/S)-1-(4-methoxy-2-nitrophenyl)-2-methyl-1-propanol (1.5 g, 67%) as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.61 (d, 1H, J=8.8 Hz, Ph-H), 7.34 (d, 1H, J=2.8 Hz, Ph-H), 7.15 (dd, 1H, J=8.8 and 2.8 Hz, Ph-H), 4.92 (dd, 1H, J=5.6 and 3.2 Hz, Ph-CH), 2.46 (br s, 1H, OH), 2.00 (m, 1H, CH), 0.97 (d, 3H, J=6.4 Hz, CH3), 0.86 (d, 3H, J=6.8 Hz, CH3).
Reaction SMILES: C(OCC[O-])C.[Na+].[Na].[NH2:9][C:10]1[N:15]=[C:14]([NH2:16])[C:13]([CH:17]=O)=[CH:12][N:11]=1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[CH2:27][C:28]#[N:29]>C(OCCO)C>[NH2:9][C:10]1[N:11]=[CH:12][C:13]2[CH:17]=[C:27]([C:21]3[C:20]([Cl:19])=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:26])[C:28]([NH2:29])=[N:16][C:14]=2[N:15]=1
Reactant: Nc1ncc(C=O)c(N)n1
Reactant: N#CCc1c(Cl)cccc1Cl
Agent: CCOCC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCOCCO
Product: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Temperature: 25 °C

Procedure:
(Prepared by the method of U.S. Pat. No. 3,534,039). To a solution of sodium 2-ethoxyethoxide prepared from 0.14 g of sodium and 60 mL of 2-ethoxyethanol was added 2.07 g of 2,4-diamino-5-pyrimidinecarboxaldehyde, and 2.79 g of 2,6-dichlorophenylacetonitrile. The mixture was heated at reflux for 4 hours, allowed to cool to room temperature, and the precipitated product was filtered and washed with diethyl ether to give 2,7-diamino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]-pyrimidine; mp 325-332° C.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.C(O)(=O)C.N1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[NH:17][CH:16]=1.[NH2:24][C:25]1C=CC=C[C:26]=1C#N>C1COCC1>[NH2:24][C:25]1[C:19]2[C:18](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:17]=[CH:16][CH:26]=1
Reactant: c1ccc2[nH]cnc2c1
Reactant: N#Cc1ccccc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Nc1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
LiHMDS (3-4 eq) was added to the benzimidazole acetate (1.0 eq) in THF (at a constant temperature ranging from −78° C. to 0° C.). After 20 minutes, a solution of the 2-aminobenzonitrile (1.1 eq) in THF was then added. The resulting mixture was allowed to warm to room temperature, stirred for 1-3 hours and was then heated to approx. 40° C.-65° C.(1 hour to 12 hours). The mixture was cooled to 0° C. and quenched with NH4Cl (aq, saturated). The aqueous phase was extracted with Ch2Cl2 or EtOAc, and the organic extracts were collected, dried (Na2SO4), and filtered. Evaporation of the solvent under reduced pressure and purification of the residue by silica gel chromatography or HPLC provided the 4-amino quinoline products.
Reaction SMILES: C(OC([C:6]1[N:7]=[C:8]([CH2:12][CH2:13][CH3:14])S[C:10]=1N)=O)C.C(O[C:18]([C:20]1[N:21]=[C:22]([CH2:32][CH2:33][CH3:34])[S:23][C:24]=1[NH:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)=[O:19])C.C(C1SC(NC2C=NC=CC=2)=C(C(O)=O)[N:42]=1)CC>>[CH3:10][C:6]1[N:7]=[C:8]([NH:42][C:18]([C:20]2[N:21]=[C:22]([CH2:32][CH2:33][CH3:34])[S:23][C:24]=2[NH:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[O:19])[CH:12]=[CH:13][CH:14]=1
Reactant: CCCc1nc(C(=O)OCC)c(N)s1
Reactant: CCCc1nc(C(=O)OCC)c(Nc2cccnc2)s1
Reactant: CCCc1nc(C(=O)O)c(Nc2cccnc2)s1
Product: CCCc1nc(C(=O)Nc2cccc(C)n2)c(Nc2cccnc2)s1

Procedure:
The title compound, MS (ISP): m/e=354.0 (M+H+), was prepared as for example 153, steps A to G. Step C was performed using butyryl chloride, and yielded butyrylamino-cyano-acetic acid ethyl ester, which was cyclized to 5-amino-2-propyl-thiazole-4-carboxylic acid ethyl ester in step D. This was used in step E to generate 2-propyl-5-(pyridin-3-ylamino)-thiazole-4-carboxylic acid ethyl ester, which was hydrolized to 2-propyl-5-(pyridin-3-ylamino)-thiazole-4-carboxylic acid in step F. Coupling as described in step G generated the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([C:11]1[C:12](=[O:32])[N:13]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[C:14]2[C:19]([C:20]=1O)=[CH:18][CH:17]=[CH:16][N:15]=2)=O.O.[NH2:34][NH2:35].C(=O)([O-])O.[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]1[C:11]2[C:12](=[O:32])[N:13]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=3)[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:20]=2[NH:35][N:34]=1
Reactant: O=C(Cc1ccccc1Cl)c1c(O)c2cccnc2n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cc3ccccc3Cl)n[nH]c2c2cccnc2n1-c1cccc(C(F)(F)F)c1
Temperature: 115 °C
Reaction time: 2 h

Procedure:
To a suspension of 3-(2-chlorophenylacetyl)-4-hydroxy-1-(3-trifluoromethylphenyl)-1,8-naphthyridin-2(1H)-one (687 mg, 1.5 mmol) produced in Synthesis Example 35 in DMF (6 mL) was added hydrazine monohydrate (purity of 80%, 240 μL), and the mixture was stirred at 110 to 120° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, washed with water, and dried to give 3-(2-chlorobenzyl)-5-(3-trifluoromethylphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one as a form of crystal (632 mg, yield 93%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:13]([O:15][C@@H:16]1[CH:21]2[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]2)[CH2:17]1)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:30][CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:33]>CCOC(C)=O>[Br-:30].[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:13]([O:15][C@@H:16]1[CH:21]2[CH2:20][CH2:19][N+:18]([CH2:31][C:32](=[O:33])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([CH2:23][CH2:22]2)[CH2:17]1)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H](C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1)OCc1ccccc1
Reactant: O=C(CBr)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](C(=O)O[C@H]1C[N+]2(CC(=O)c3ccccc3)CCC1CC2)c1ccccc1)OCc1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 75.8 %

Procedure:
To a solution of (R)—((R)-quinuclidin-3-yl) 2-(benzyloxy-carbonylamino)-2-phenylacetate (40 mg, 0.10 mmol) in EtOAc (3 ml), 2-bromo-1-phenylethanone (22.2 mg, 0.11 mmol) was added and the reaction was stirred at RT for 15 hours, and then the solvent was evaporated. The crude was purified by silica gel flash chromatography (DCM/MeOH=93/7) to obtain (R)-3-((R)-2-(benzyloxycarbonylamino)-2-phenylacetoxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane bromide (45.0 mg; 74.8% yield).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][OH:6])[CH3:2].[H-].[Na+].Cl[C:10]1[C:14]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:13][S:12][N:11]=1.O>O1CCCC1>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:10]1[C:14]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:13][S:12][N:11]=1)[CH3:2]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOCCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-ethoxyethanol (1.08 g, 12 mmol) and sodium hydride (410 mg, 12 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (790 mg, 4 mmol) in dry tetrahydrofuran. The mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[CH2:8]([O:15][C:16]1[CH:17]=[C:18]([CH2:24][C@H:25]([NH:30][C:31](=[O:43])[C@@H:32]([NH:35]C(OC(C)(C)C)=O)[CH2:33][OH:34])[C:26]([O:28][CH3:29])=[O:27])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[NH2:35][C@@H:32]([CH2:33][OH:34])[C:31]([NH:30][C@@H:25]([CH2:24][C:18]1[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:16]([O:15][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:17]=1)[C:26]([O:28][CH3:29])=[O:27])=[O:43].[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2]
Reactant: COC(=O)[C@H](Cc1ccc(OC)c(OCc2ccccc2)c1)NC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(OC)c(OCc2ccccc2)c1)NC(=O)[C@@H](N)CO

Procedure:
TFA (20 mL) was added to a solution of (S)-methyl 3-(3-(benzyloxy)-4-methoxyphenyl)-2-((S)-2-((tert-butoxycarbonyl)amino)-3-hydroxypropanamido)propanoate (4.4 g, 8.7 mmol) in CH2Cl2 (50 mL) at 0° C. with stirring. The mixture was stirred for 1 h and then concentrated to dryness. The residue was azeotroped three times with EtOAc (20 mL for each portion) to remove residual TFA to afford crude (S)-methyl 2-((S)-2-amino-3-hydroxypropanamido)-3-(3-(benzyloxy)-4-methoxyphenyl)propanoate as its TFA salt.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([OH:19])=O)=[CH:13][N:12]=2)[CH:4]=1)[CH3:2].[CH:20]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([NH:25][C:17]([C:14]2[CH:15]=[CH:16][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[N:12][CH:13]=2)=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NC1CCCC1
Reactant: CCc1cc(-c2ccc(C(=O)O)cn2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(C(=O)NC3CCCC3)cn2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[2,3′]bipyridinyl-5-carboxylic acid and cyclopentyl amine to afford the title compound. MS: m/e=326 (M+H).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN(C=O)C.[Br:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19](F)[CH:18]=1>C1COCC1>[CH2:3]([O:10][C:19]1[CH:18]=[C:17]([Br:16])[CH:22]=[C:21]([F:23])[CH:20]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Fc1cc(Br)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
Sodium hydride (80% oil dispersion, 6.0 g, 201 mmol) was added slowly to a solution of benzyl alcohol (16 mL, 155 mmol) in THF (310 mL) at 0° C. DMF (300 mL) was added slowly and the reaction mixture was stirred until all of the NaH dissolved and gas evolution ceased. A solution of 1-bromo-3,5-difluorobenzene (30 g, 155 mmol) in THF (30 mL) was added and the reaction mixture was stirred for 30 min at ambient temperature. The reaction was quenched with saturated aqueous NH4Cl, and the reaction mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with saturated aqueous NH4Cl and brine, dried over MgSO4, filtered, and concentrated in vacuo to give a yellow liquid. 3-benzyloxy-5-fluorobromobenzene (28 g) was isolated by chromatography on silica gel (5% ethyl acetate, hexanes). Step 2. 4-[(3-benzyloxy-5-fluorophen-1-yl)oxomethyl]tetrahydropyran.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=[N:23][NH2:24])[NH2:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>CS(C)=O.C(Cl)Cl>[C:31]([NH:24]/[N:23]=[C:21](\[C:18]1[N:17]=[C:16]2[N:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[N:13]=[N:14][C:15]2=[N:20][CH:19]=1)/[NH2:22])(=[O:33])[CH3:32]
Reactant: NN=C(N)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(=O)N/N=C(/N)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reaction time: 8 h
Yield: 70.6 %

Procedure:
To a solution of 1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine-6-carbohydrazonamide (25 mg, 0.078 mmol) in DMSO (1 mL) and DCM (2.0 mL), was added pyridine (6.19 mg, 0.078 mmol) and acetic anhydride (10.39 mg, 0.102 mmol). After stirring overnight, the reaction mixture was filtered. The solid was washed with EtOH, H2O and EtOH to give 19.9 mg of title compound in 67% yield. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.48 (d, 1H), 8.88 (d, 1H), 8.34 (d, 1H), 8.05 (s, 1H), 8.01 (d, 1H), 7.86 (d, 1H), 7.53 (dd, 1H), 6.20 (s, 2H), 2.24 (s, 1H), 2.00 (s, 1H). LCMS (method B): [MH]+=362, tR=1.60 min.
Reaction SMILES: [OH:1][C:2]1([C@@H:8]2[CH2:13][C@H:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.[C:35]([C:39]1[N:44]=[C:43]([NH:45][CH2:46][CH2:47][CH2:48][O:49][CH3:50])[C:42]([C:51]([Cl:53])=[O:52])=[CH:41][N:40]=1)([CH3:38])([CH3:37])[CH3:36]>ClCCCl>[ClH:53].[ClH:53].[C:35]([C:39]1[N:44]=[C:43]([NH:45][CH2:46][CH2:47][CH2:48][O:49][CH3:50])[C:42]([C:51]([N:14]([C@H:12]2[CH2:13][C@@H:8]([C:2]3([OH:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)[CH2:9][NH:10][CH2:11]2)[CH2:15][CH:16]([CH3:17])[CH3:18])=[O:52])=[CH:41][N:40]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)CN[C@H]1C[C@@H](C2(O)CCCCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: COCCCNc1nc(C(C)(C)C)ncc1C(=O)Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@@H]1CNC[C@H](C2(O)CCCCC2)C1
Product: Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 0.8 %

Procedure:
tert-Butyl (3R,5S)-3-(1-hydroxycyclohexyl)-5-[(2-methylpropyl)amino]piperidine-1-carboxylate (0.92 g) and N,N-diisopropylethylamine (1.0 g) were dissolved in 1,2-dichloroethane (10 ml), 2-tert-butyl-4-[(3-methoxypropyl)amino]pyrimidine-5-carbonyl chloride (0.74 g) was added under ice-cooling, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, and diluted with aqueous calcium carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in 4 N hydrogen chloride-ethyl acetate (1 ml), and the mixture was stirred at room temperature for 0.5 hr. The reaction mixture was concentrated and purified by HPLC. The concentrate was dissolved in 4 N hydrogen chloride-ethyl acetate (1 ml) and concentrated to give the object compound (5.9 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:6]([C:8]1[N:12]([CH3:13])[C:11]([CH2:14][C:15]([O:17]CC)=[O:16])=[CH:10][C:9]=1[CH3:20])=[O:7].C(I)CCCCC>>[CH2:14]([C:11]1[N:12]([CH3:13])[C:8]([C:6](=[O:7])[C:5]2[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:3]([O:2][CH3:1])[CH:4]=2)=[C:9]([CH3:20])[CH:10]=1)[CH3:15].[CH2:11]([CH2:14][C:15]([O-:17])=[O:16])[CH2:10][CH2:9][CH2:8][CH2:6][CH3:5]
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(OC)c(OC)c2)n1C
Solvent: CCCCCCI
Product: CCCCCCCC(=O)[O-]
Product: CCc1cc(C)c(C(=O)c2ccc(OC)c(OC)c2)n1C

Procedure:
The alkylation procedure of Example 77A is performed upon ethyl 5-(3',4'-dimethoxybenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example 90), using an equivalent quantity of n-hexyl iodide instead of methyl iodide used in Example 77A to yield ethyl 5-(3',4'-dimethoxybenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetate.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([C:9]([F:12])([F:11])[F:10])=[C:7](CC#N)[CH:6]=[N:5]2)[CH2:3][CH2:2]1.[OH-:16].[Na+].[CH3:18][CH2:19][OH:20]>>[CH:1]1([N:4]2[C:8]([C:9]([F:12])([F:11])[F:10])=[C:7]([CH2:18][C:19]([OH:16])=[O:20])[CH:6]=[N:5]2)[CH2:3][CH2:2]1
Reactant: CCO
Reactant: [OH-]
Reactant: N#CCc1cnn(C2CC2)c1C(F)(F)F
Agent: [Na+]
Product: O=C(O)Cc1cnn(C2CC2)c1C(F)(F)F
Temperature: 60 °C
Yield: 85 %

Procedure:
To a solution of (1-Cyclopropyl-5-trifluoromethyl-1H-pyrazol-4-yl)-acetonitrile (Preparation 98, 700 mg, 3.25 mmol) in EtOH (15 mL) was added aqueous 1N NaOH (15 mL). The resulting solution was heated at 60° C. for 16 hours. The mixture was concentrated in vacuo and the residue was dissolved in water (10 mL) and washed with EtOAc. The aqueous layer was acidified to pH5 using 1N HCl and extracted with 10% IPA in DCM (4×30 mL). The organic layer was dried (Na2SO4) and evaporated in vacuo to afford the title compound as a solid (85%, 650 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=C)[CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])([CH3:4])([CH3:3])[CH3:2].O.C[N+]1([O-])CC[O:25]CC1.[O-]S([O-])(=S)=O.[Na+].[Na+]>CC(C)=O.[Os](=O)(=O)(=O)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:15]=[O:25])[CH:12]=[C:11]([Cl:17])[C:10]=1[F:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cc(C=O)cc(Cl)c1F
Reaction time: 1 h

Procedure:
To a solution of (3-chloro-2-fluoro-5-vinyl-benzyl)-carbamic acid tert-butyl ester (2.7 g, 9.5 mmol) in acetone (20 mL) was added N-methylmorpholine-N-oxide monohydrate (1.5 g, 11 mmol) and a solution of 4% aq. osmiumtetraoxide (3.7 mL, 0.5 mmol). The reaction was stirred for 1 h, saturated aqueous Na2S2O3-solution was added and stirring was continued for one hour. After extraction with EtOAc and removal of the solvent in vacuo, the residue was dissolved in acetone/water (3:1, 40 mL) and NalO4 (4.0 g, 19 mmol) was added. After stirring for 2 h at ambient temperature, the reaction mixture was filtered, washed with EtOAc, extracted with EtOAc, dried (Na2SO4) and the solvent was removed in vacuo to give the title compound which was used without further purification. tR (HPLC conditions c): 5.22 min.
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[NH:6][C:5](=[O:14])[CH:4]=1)[NH2:2].[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][CH:20]=[C:19]2[CH:26]=O.[CH3:28][N:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[CH:34]=O>>[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][CH:20]=[C:19]2[CH2:26][N:2]1[C:34]([C:30]2[N:29]([CH3:28])[CH:33]=[CH:32][CH:31]=2)=[C:4]2[C:3]([N:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7](=[O:13])[NH:6][C:5]2=[O:14])=[N:1]1
Reactant: CC(C)Cn1c(NN)cc(=O)[nH]c1=O
Reactant: Cn1cccc1C=O
Reactant: O=Cc1ccnc2ccc(Cl)cc12
Product: CC(C)Cn1c(=O)[nH]c(=O)c2c(-c3cccn3C)n(Cc3ccnc4ccc(Cl)cc34)nc21

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutylpyrimidine-2,4(1H,3H)-dione, and condensing first with 6-chloroquinoline-4-carbaldehyde, followed by 1-methyl-2-pyrrolecarboxaldehyde. ES M+H+=488.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1I.[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15].[Li+].[Cl-].CCOC(C)=O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH2:15][CH:14]=[CH2:13]
Reactant: O=C1OCc2c1ccc(Br)c2I
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CCc1c(Br)ccc2c1COC2=O
Temperature: 95 °C

Procedure:
A mixture of 5-bromo-4-iodo-2-benzofuran-1(3H]-one (2.42 g, 7.13 mmol), allyltributyltin (2.36 g, 7.13 mmol), LiCl (1.50 g, 35.7 mmol) and Pd (PPh3)4 (200 g, 0.173 mmol) in toluene (50 mL) was heated at 90-100° C. under N2 overnight; LC indicated that reaction had gone to completion, to the solution was poured EtOAc (100 mL) and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated to dryness, absorbed into silica gel and was then separated over silica gel column to give 5-bromo-4-prop-2-en-1-yl-2-benzofuran-1(3H)-one. 1H-NMR (400 MHz, CDCl3) δ ppm 7.795 (d, J=8 Hz, 1H), 7.680 (d, J=8 Hz, 8.5 Hz, 1H), 5.938-5.925 (m, 1H), 5.302 (s, 2H), 5.192-5.172 (m, 1H), 5.075-5.041 (m, 1H), 3.611-3.599 (m, 2H)