Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[CH:40]=[C:39]([C:41]([CH2:44][CH3:45])([CH3:43])[CH3:42])[CH:38]=[CH:37][C:7]=1[O:8][CH:9]([CH2:35][CH3:36])[C:10]([NH:12][C:13]1[CH:14]=[C:15]([CH:32]=[CH:33][CH:34]=1)[C:16]([NH:18][C:19]1[CH:20]=[CH:21][C:22]2[C:23]([C:30]=1[OH:31])=[CH:24][CH:25]=[CH:26][C:27](=[O:29])[N:28]=2)=[O:17])=[O:11])([CH2:4][CH3:5])([CH3:3])[CH3:2].S(Cl)([Cl:49])(=O)=O.C(OCC)(=O)C.[Cl-].[Na+]>C(Cl)Cl>[Cl:49][C:21]1[C:22]2[C:23](=[CH:24][CH:25]=[CH:26][C:27](=[O:29])[N:28]=2)[C:30]([OH:31])=[C:19]([NH:18][C:16](=[O:17])[C:15]2[CH:32]=[CH:33][CH:34]=[C:13]([NH:12][C:10](=[O:11])[CH:9]([O:8][C:7]3[CH:37]=[CH:38][C:39]([C:41]([CH2:44][CH3:45])([CH3:42])[CH3:43])=[CH:40][C:6]=3[C:1]([CH2:4][CH3:5])([CH3:3])[CH3:2])[CH2:35][CH3:36])[CH:14]=2)[CH:20]=1
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cccc(C(=O)Nc2ccc3nc(=O)cccc3c2O)c1
Reactant: O=S(=O)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cccc(C(=O)Nc2cc(Cl)c3nc(=O)cccc3c2O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 30 ml of methylene chloride was dispersed 6 g of the 7-{3-[2-(2,4-di-t-amylphenoxy)butanoylamino]benzoylamino}-6-hydroxybenzazepin-2-one prepared in (6) above, and 0.84 ml of sulfuryl chloride was added drop-wise to the dispersion at room temperature. After stirring at room temperature for 2 hours, ethyl acetate and a saturated aqueous solution of sodium chloride were added thereto to effect extraction. The extract was concentrated under reduced pressure, and the residue was dispersed in 30 ml of acetonitrile and 15 ml of ethyl acetate. The dispersion was heat-refluxed, followed by cooling. The precipitated crystals were collected by filtration and dried to obtain 5.8 g of the desired coupler having a melting point of 234° to 236° C.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[C:12]2[CH2:13][CH2:14][O:15][C:11]=2[C:10]([C:16]([OH:18])=[O:17])=[CH:9][C:8]=1[Cl:19].[CH3:20]O.N>CO>[NH2:6][C:7]1[C:12]2[CH2:13][CH2:14][O:15][C:11]=2[C:10]([C:16]([O:18][CH3:20])=[O:17])=[CH:9][C:8]=1[Cl:19]
Reactant: Nc1c(Cl)cc(C(=O)O)c2c1CCO2
Reactant: CO
Agent: N
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Cl)c(N)c2c1OCC2
Yield: 81 %

Procedure:
Sulfuric acid (18 ml) was added dropwise to cooled methanol (90 ml). 4-Amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid (20 g) was added to the mixture which was subsequently stirred and refluxed for 3 hours. The reaction mixture was cooled and alkalized with CH3OH/NH3. The solvent was evaporated and the residue stirred in water. The precipitate was filtered off and washed with water and DIPE. The remaining solid was dried, yielding 17.2 g (81%) of methyl 4-amino-5-chloro-2,3-di-hydro-7-benzofurancarboxylate (intermediate 1; mp. 135.4° C.).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.[CH3:27][O:28][C:29]1[N:34]=[C:33](/[CH:35]=[CH:36]/[C:37]([OH:39])=O)[CH:32]=[CH:31][C:30]=1[N:40]1[CH:44]=[C:43]([CH3:45])[N:42]=[CH:41]1.[NH2:46][N:47]1[CH2:52][CH2:51][CH2:50][CH:49]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[C:59]([F:62])([F:61])[F:60])[C:48]1=[O:63].C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C.C(Cl)CCl>[CH3:27][O:28][C:29]1[N:34]=[C:33](/[CH:35]=[CH:36]/[C:37]([NH:46][N:47]2[CH2:52][CH2:51][CH2:50][CH:49]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=3[C:59]([F:60])([F:61])[F:62])[C:48]2=[O:63])=[O:39])[CH:32]=[CH:31][C:30]=1[N:40]1[CH:44]=[C:43]([CH3:45])[N:42]=[CH:41]1
Reactant: COc1nc(/C=C/C(=O)O)ccc1-n1cnc(C)c1
Reactant: NN1CCCC(c2ccccc2C(F)(F)F)C1=O
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1nc(/C=C/C(=O)NN2CCCC(c3ccccc3C(F)(F)F)C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 84.8 %

Procedure:
EDC (834 mg), HOBT (588 mg) and IPEA (2.03 mL) were added to a suspension of (E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic acid trifluoroacetate (1.42 g) and 1-amino-3-(2-trifluoromethylphenyl)piperidin-2-one (750 mg) in DMF (30 mL). After stirring at room temperature for 14 hours, a saturated sodium bicarbonate solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: ethyl acetate-methanol system) to obtain 1.23 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([S:12][C:13]1[N:17]3[N:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]3=[N:15][N:14]=1)=[CH:7][CH:6]=2.[CH3:23][N:24]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[N:25]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[CH3:23][N:24]1[CH:28]=[C:27]([C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][C:8]([S:12][C:13]2[N:17]4[N:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]4=[N:15][N:14]=2)=[CH:7][CH:6]=3)[CH:26]=[N:25]1
Reactant: Cc1ccc2nnc(Sc3ccc4ncc(Br)cc4c3)n2n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc2nnc(Sc3ccc4ncc(-c5cnn(C)c5)cc4c3)n2n1
Yield: 27.5 %

Procedure:
A microwave vessel was charged with 3-bromo-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinoline (40 mg, 0.107 mmol), 1-methyl-4-pyrazoleboronic acid pinacol ester (27 mg, 0.129 mmol), and dichlorobis(triphenylphosphine) palladium(0) (4 mg, 0.005 mmol). 1,2-Dimethoxyethane (0.5 mL) and a 2 M aqueous solution of sodium carbonate (0.5 mL) were added. The vessel was capped and microwaved at 120° C. for 30 min. The organic layer was separated, the aqueous layer was extracted with 10% methanol/dichloromethane (2×), and the combined organics were adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-6% methanol/dichloromethane afforded 28 mg of an off white solid. The solid was further purified by mass-triggered HPLC (5-95% CH3CN/H2O, 0.1% HCOOH modifier) to provide 11 mg of 3-(1-methyl-1H-pyrazol-4-yl)-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinoline as a white solid (28% yield).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].CC[O-].[Na+].[Cl:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26]Cl)[N:21]=1>CN(C=O)C.C(OCC)C>[Cl:18][CH2:19][C:20]1[N:21]=[C:22]([CH3:26])[C:23]([O:8][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][C:1](=[O:3])[CH3:2])=[CH:24][CH:25]=1
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: ClCc1cccc(CCl)n1
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(=O)Oc1ccccc1C(=O)Oc1ccc(CCl)nc1C
Reaction time: 168 h
Yield: 59.9 %

Procedure:
To a solution of acetylsalicylic acid (1.6 g, 8.88 mmoles) in N,N′-dimethylformamide (20 ml) and under stirring, sodium ethylate (0.64 g, 8.88 mmoles) is added. After 30 minutes the obtained solution is added to a solution of 2,6-bis-(chloromethyl)pyridine (4.72 g, 26.81 mmoles) in N,N′-dimethylformamide (20 ml). The solution is left at room temperature for 7 days, under stirring, then it is diluted with ethyl ether and washed with water. The separated organic phases are anhydrified with sodium sulphate and the solvent is evaporated at reduced pressure. The reaction crude product is purified by chromatography on silica gel eluting with n-hexane/ethyl acetate 7/3. 1.7 g of the product are obtained as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:14]2[CH:18]3[CH2:19][CH2:20][CH:15]2[CH2:16][CH2:17]3)=[N:8][C:9]=1[C:10]([F:13])([F:12])[F:11])([O-])=O>[Pd]>[CH:15]12[N:14]([C:7]3[N:8]=[C:9]([C:10]([F:13])([F:11])[F:12])[C:4]([NH2:1])=[CH:5][CH:6]=3)[CH:18]([CH2:17][CH2:16]1)[CH2:19][CH2:20]2
Reactant: O=[N+]([O-])c1ccc(N2C3CCC2CC3)nc1C(F)(F)F
Agent: [Pd]
Product: Nc1ccc(N2C3CCC2CC3)nc1C(F)(F)F
Reaction time: 16 h
Yield: 80.3 %

Procedure:
A flask charged with 7-[5-nitro-6-(trifluoromethyl)-2-pyridyl]-7-azabicyclo[2.2.1]heptane (530 mg, 1.845 mmol) and 10% Pd/C (53 mg, 0.4980 mmol) was flushed with nitrogen followed by evacuating under vacuum. Ethanol (6 mL) was added under inert atmosphere and the flask fitted with a hydrogen balloon. After 16 h of vigorous stirring the Pd/C was removed by filtration and solvent was removed under reduced pressure. The crude material was purified via silica gel chromatography (0-10% ethyl acetate in hexanes) to provide 6-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)pyridin-3-amine (381 mg, 80% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 7.17 (d, J=8.9 Hz, 1H), 6.97 (d, J=8.9 Hz, 1H), 5.03 (s, 2H), 4.29 (s, 2H), 1.59 (t, J=3.4 Hz, 4H), 1.37 (d, J=6.7 Hz, 4H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[CH:29][C:30]([C:33]#[N:34])=[N:31][CH:32]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[CH:28]=[CH:29][C:30]([C:33]#[N:34])=[N:31][CH:32]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: N#Cc1ccc(Br)cn1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: N#Cc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (710 mg, 2.0 mmol) and commercially available 5-bromo-2-cyano-pyridine (366 mg, 2.0 mmol) according to general procedure II. Obtained as an orange solid (730 mg, 80%). MS (EI) 457.1 [(M)+]; mp 212° C.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH2:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][C:3]=1[NH2:4].[N+:15]([C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1)([O-:17])=[O:16]>>[N+:15]([C:18]1[CH:23]=[C:22]([C:2]2[CH:8]=[C:7]([CH2:9][CH:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH:6]=[CH:5][C:3]=2[NH2:4])[CH:21]=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Nc1ccc(CC2CCCC2)cc1Br
Product: Nc1ccc(CC2CCCC2)cc1-c1cccc([N+](=O)[O-])c1

Procedure:
2-bromo-4-(cyclopentylmethyl)aniline and 3-nitrobenzene boronic acid can be combined to form 2-(3-nitrophenyl)-4-(cyclopentylmethyl)aniline.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:22]=[C:21]2[C:12]([N:13]3[C:18]([CH2:19][O:20]2)=[N:17][NH:16][C:15](=[O:23])[CH:14]3[CH3:24])=[CH:11][C:10]=1[N+:25]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Ni]>[NH2:25][C:10]1[CH:11]=[C:12]2[C:21](=[CH:22][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[O:20][CH2:19][C:18]1[N:13]2[CH:14]([CH3:24])[C:15](=[O:23])[NH:16][N:17]=1
Reactant: CC1C(=O)NN=C2COc3cc(OCc4ccccc4)c([N+](=O)[O-])cc3N21
Agent: [Ni]
Solvent: CO
Product: CC1C(=O)NN=C2COc3cc(OCc4ccccc4)c(N)cc3N21
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.6 %

Procedure:
To a solution of 7-benzyloxy-4-methyl-6-nitro-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.14 g, 0.38 mmol) in MeOH (10 mL) was added Raney-Ni (0.03 g). Then the mixture was stirred under an atmosphere of H2 (1 atm) at rt for 2 h. The reaction mixture was filtered and washed with 10% MeOH/DCM (3×10 mL). The filtrate was concentrated in vacuo to give 6-amino-7-benzyloxy-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.065 g, 54%), which was used in the next step directly without further purification. TLC (eluting with 50% EtOAc in petroleum ether) Rf=0.3.
Reaction SMILES: N(C(C)(C)C#N)=NC(C)(C)C#N.[CH3:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1.[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: Cc1ncccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccnc1CBr
Temperature: 25 °C
Yield: 37.3 %

Procedure:
2,2′-azobis(isobutyronitrile) (2.7 g, 16.4 mmol) was added to a solution of 2-methyl-3-nitropyridine (12.97 g, 92.6 mmol) prepared in Step 1 and N-bromosuccinimide (23.06 g, 130 mmol) in carbon tetrachloride (100 ml) and then the reaction mixture was refluxed for 3 days. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate (100 ml) and then washed with a saturated sodium bicarbonate solution and a saturated sodium thiosulfate solution. The organic layer was dried on anhydrous magnesium sulfate and then purified with silica gel column chromatography (dichloromethane/n-hexane=2/1, v/v) to give 7.5 g of the titled compound as brown oil.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[OH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[OH:17].[OH-].[K+]>O>[O:6]1[CH:3]([CH2:4][OH:5])[CH2:1][O:17][C:8]2[CH:9]=[CH:10][C:11]3[C:16]([C:7]1=2)=[CH:15][CH:14]=[CH:13][CH:12]=3
Reactant: ClCC1CO1
Reactant: Oc1ccc2ccccc2c1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: OCC1COc2ccc3ccccc3c2O1
Reaction time: 2.5 h
Yield: 74.1 %

Procedure:
Epichlorohydrin (2.32 g) was added dropwise to a stirred solution of 1,2-dihydroxynaphthalene (4.0 g) and potassium hydroxide (4.0 g) in water (32 ml) and the resulting mixture stirred at 60°-80° C. for 2.5 hours then poured into water (100 ml). The product was extracted into ether (6×100 ml), a small volume of methanol being added to aid solubility. The combined extracts were washed with aqueous sodium hydroxide solution (1M), then water, and dried over magnesium sulphate. The solvent was removed in vacuo to give crude 1-(naphtho[1,2-b]dioxan-2-yl)methanol (4.0 g) as a dark oil which was used without further purification.
Reaction SMILES: [C:1]([C:3]1[C:12]([NH:13][CH:14]([CH3:16])[CH3:15])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:17])[CH:4]=1)#[N:2].OO.C(=O)([O-])[O-:21].[K+].[K+]>CS(C)=O>[NH2:2][C:1]([C:3]1[C:12]([NH:13][CH:14]([CH3:15])[CH3:16])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:17])[CH:4]=1)=[O:21]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(NC(C)C)c(C#N)cc1C
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1cc(NC(C)C)c(C(N)=O)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 261.3 %

Procedure:
Methyl 4-cyano-5-(isopropylamino)-2-methylbenzoate (224 mg, 0.96 mmol) was dissolved in DMSO (2 mL) and cooled in a cold water bath. 30% Aqueous hydrogen peroxide (0.2 mL) and potassium carbonate (42.6 mg, 0.31 mmol) was added, and the mixture was stirred at ambient temperature for 1 h. The reaction mixture was partitioned between ethyl acetate and 10% aqueous lithium chloride. The aqueous portion was extracted with ethyl acetate. The combined organic portion was dried over sodium sulfate, then filtered and concentrated to a yellow oil which was purified by column chromatography (silica gel, 15-30% ethyl acetate in hexanes to afford methyl 4-aminocarbonyl-5-(isopropylamino)-2-methylbenzoate (202 mg, 0.81 mmol, 83% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.35 (d, 1H), 7.26 (d, 1H), 7.24-7.22 (m, 2H), 5.70 (br s, 1H), 3.90 (s, 3H), 3.75-3.68 (m, 1H), 2.42 (s, 3H), 1.26-1.24 (m, 6H); MS (EI) for C13H18N2O3: 251 (MH+).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:30])[CH2:18][C:19]3[CH:20]=[N:21][C:22](Cl)=[C:23]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:24]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:31][C:32]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[CH:34][N:33]=1.C([O-])([O-])=O.[Na+].[Na+].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.C(O)C.O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:30])[CH2:18][C:19]3[CH:24]=[C:23]([S:25]([CH3:28])(=[O:27])=[O:26])[C:22]([C:36]4[CH:35]=[CH:34][N:33]=[C:32]([CH3:31])[CH:37]=4)=[N:21][CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: CC(=O)N1CCN(c2ccc(NC(=O)Cc3cnc(Cl)c(S(C)(=O)=O)c3)nc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3cnc(-c4ccnc(C)c4)c(S(C)(=O)=O)c3)nc2)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a sealed tube were added N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(6-chloro-5-(methylsulfonyl)pyridin-3-yl)acetamide 197-7 (30 mg, 0.07 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine 183-2 (22 mg, 0.10 mmol), Pd(PPh3)4 (4 mg, 0.003 mmol), Na2CO3 (22 mg, 0.20 mmol), Toluene (0.4 mL), H2O (0.4 mL) and ethanol (0.1 mL). The reaction mixture was stirred at 100° C. overnight. After cooling to room temperature, the solvents were removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(2′-methyl-3-(methylsulfonyl)-2,4′-bipyridin-5-yl)acetamide 197. MS m/z 509.2 (M+1); 1H NMR 400 MHz (MeOD) δ 8.81 (d, 1H), 8.52 (d, 1H), 8.49 (d, 1H), 7.97 (s, 1H), 7.87 (d, 1H), 7.47 (s, 1H) 7.41 (dd, 1H), 7.37 (dd, 1H), 3.95 (s, 2H), 3.68 (t, 2H), 3.63 (t, 2H), 3.15 (t, 2H), 3.09 (t, 2H), 2.92 (s, 3H), 2.57 (s, 3H), 2.09 (s, 3H).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([CH3:24])[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:25][CH2:26][C:27]([OH:29])=[O:28].C[O-].[Na+]>>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[C:7]([CH3:24])=[N:6][C:5]([C:3]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1nc(C)c2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: Cc1nc(C(=O)NCC(=O)O)c(O)c2ccn(Cc3ccccc3)c(=O)c12
Temperature: 25 °C
Yield: 74.2 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-1-methyl-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (25 mg, 0.077 mmol), glycine (770 mg, 10.3 mmol) and NaOMe solution (15 mL, 7.7 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between water and EtOAc. 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The crude was chromatographed (5-70% EtOAc/hexanes+2% AcOH) to give 21 mg of the title compound as a pale yellow solid. MS: (+) m/z 367.98 (M+1).
Reaction SMILES: C1C(=O)N([O:8][C:9]([O:11][CH2:12][CH:13]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)=O)C(=O)C1.[NH2:26][C@H:27]([C:32]([OH:34])=[O:33])[CH2:28][C:29]([OH:31])=[O:30].C([O-])([O-])=O.[Na+].[Na+].Cl>O.O1CCOCC1>[C:9]([NH:26][C@H:27]([C:32]([OH:34])=[O:33])[CH2:28][C:29]([OH:31])=[O:30])([O:11][CH2:12][CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]2[C:25]1=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:8]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
Forty-five g (0.134 M, 0.96 eq) of Fmoc-Osu was added to 20 g (0.15 M, 1 eq) of aspartic acid and 20 g of Na2CO3 dissolved in 400 mL of water and 200 mL of dioxane. The mixture was stirred for 2 hrs while the pH was maintained at about 9 by the addition of small amounts of Na2CO3. Then the cloudy white mixture was poured into 500 mL of ice water containing 40 mL of conc HCl. The white solid was extracted with 500 mL EtOAc and this was mixed with 500 mL of hexane. The mixture was chilled overnight and stirred the next day to give 38 g of Fmoc-aspartic acid as crystals (71% yield) upon filtration and air drying. 10 g (0.28 M) of this product was dissolved in 200 mL of methanol and 20 mL of conc H2SO4 was added. The solution was allowed to stand overnight. The mixture was poured into 1 L of water and filtered. The resulting white solid was dried and redissolved in EtOAc. Slow addition of hexane and chilling gave 9 g (83% yield) of product as white needles, mp 78-80°. [a]d =-13.9°.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[I:8][C:9]1[CH:10]=[C:11]([N:15]2[C:23](=[O:24])[C:22]3[C@@H:21]4[C:25]([CH3:27])([CH3:26])[C@@:18]([CH3:28])([CH2:19][CH2:20]4)[C:17]=3[NH:16]2)[CH:12]=[CH:13][CH:14]=1>CO.[OH-].[Na+].O>[I:8][C:9]1[CH:10]=[C:11]([N:15]2[C:23](=[O:24])[C:22]3[C@@H:21]4[C:25]([CH3:27])([CH3:26])[C@@:18]([CH3:28])([CH2:19][CH2:20]4)[C:17]=3[N:16]2[CH3:5])[CH:12]=[CH:13][CH:14]=1
Reactant: COS(=O)(=O)OC
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3cccc(I)c3)c(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1c2c(c(=O)n1-c1cccc(I)c1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
Dimethyl sulfate (0.6 mL, 6.3 mmol) was added to a mixture of (4S,7R)-2-(3-iodo-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 18; 1.62 g, 4.1 mmol) in methanol (10 mL) and 1 M NaOH (20 mL). The mixture was stirred at room temperature overnight and then further portions of dimethyl sulfate (0.6 mL, 6.3 mmol) were added immediately, after 2 h, and after 5 h. The mixture was stirred at room temperature over the weekend, and it was then diluted with water and extracted with ethyl acetate (2×125 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried (magnesium sulfate), filtered, evaporated, and purified using an Analogix Intelliflash 280 system (Analogix, Inc., Burlington, Wis.) with an RS-90 column, eluting with 0-100% ethyl acetate/hexanes to give (4S,7R)-2-(3-iodo-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (620 mg, 38%), as a white solid, (4S,7R)-2-(3-iodo-phenyl)-3-methoxy-7,8,8-trimethyl-4,5,6,7-tetrahydro-2H-4,7-methano-indazole (606 mg, 37%) as a yellow solid and unreacted starting material (140 mg, 9%). ES(+)-MS (M+H) 409.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:17][CH2:16][C:15]3[C:14]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]4[CH3:24])=[N:13][C:12]([C:25]4[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:34][CH2:35][CH3:36])=[O:33])=[CH:27][CH:26]=4)=[N:11][C:10]=3[CH2:9]2)[N:3]=1.CO>[Pd]>[CH2:35]([NH:34][C:32]([NH:31][C:28]1[CH:29]=[CH:30][C:25]([C:12]2[N:13]=[C:14]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]3[CH3:24])[C:15]3[CH2:16][CH2:17][N:8]([C:4]4[N:3]=[CH:2][N:7]=[CH:6][N:5]=4)[CH2:9][C:10]=3[N:11]=2)=[CH:26][CH:27]=1)=[O:33])[CH3:36]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(c2ncnc(Cl)n2)C3)cc1
Agent: [Pd]
Solvent: CO
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(c2ncncn2)C3)cc1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
Step 2—Synthesis of vg: (S)-1-(4-(7-(4-chloro-1,3,5-triazin-2-yl)-4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)-3-ethylurea (0.147 g, 0.000288 mol), Palladium on Carbon 10% (0.1:0.9, Palladium:carbon black, 0.116 g), and Methanol (10.0 mL, 0.247 mol) were combined under N2 then purged with hydrogen, heated at 65° C. and stirred overnight. The reaction mixture was purged with N2, added celite, filtered through celite, filtered through a disc filter, concentrated, and purified by HPLC. 1H NMR (500 MHz, DMSO) δ 8.71 (s, 1H), 8.67 (d, J=2.0, 2H), 8.20 (d, J=8.8, 2H), 7.49 (d, J=8.8, 2H), 6.21 (t, J=5.6, 1H), 4.91 (d, J=18.6, 1H), 4.77 (d, J=18.6, 1H), 4.20-4.02 (m, 2H), 3.87 (d, J=12.5, 2H), 3.69 (d, J=8.4, 1H), 3.66-3.56 (m, 3H), 3.47-3.36 (m, 1H), 3.17-3.06 (m, 2H), 2.76 (s, 2H), 1.25 (d, J=6.7, 3H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+476.2 (M+H)+.